Guideline Ibd

Guidelines for the management of inflammatorybowel disease in adults

Craig Mowat,1 Andrew Cole,2 Al Windsor,3 Tariq Ahmad,4 Ian Arnott,5

Richard Driscoll,6 Sally Mitton,7 Tim Orchard,8 Matt Rutter,9 Lisa Younge,10

Charlie Lees,5 Gwo-tzer Ho,5 Jack Satsangi,5 Stuart Bloom,11 on behalf of the IBDSection of the British Society of Gastroenterology

ABSTRACTThe management of inflammatory bowel diseaserepresents a key component of clinical practice formembers of the British Society of Gastroenterology(BSG). There has been considerable progress inmanagement strategies affecting all aspects of clinicalcare since the publication of previous BSG guidelines in2004, necessitating the present revision.Key components of the present document worthy ofattention as having been subject to re-assessment, andrevision, and having direct impact on practice include:< The data generated by the nationwide audits of

inflammatory bowel disease (IBD) management in theUK in 2006, and 2008.

< The publication of ‘Quality Care: service standards forthe healthcare of people with IBD’ in 2009.

< The introduction of the Montreal classification forCrohn’s disease and ulcerative colitis.

< The revision of recommendations for the use ofimmunosuppressive therapy.

< The detailed analysis, guidelines andrecommendations for the safe and appropriate use ofbiological therapies in Crohn’s disease and ulcerativecolitis.

< The reassessment of the role of surgery in diseasemanagement, with emphasis on the importance ofmulti-disciplinary decision-making in complex cases.

< The availablity of new data on the role ofreconstructive surgery in ulcerative colitis.

< The cross-referencing to revised guidelines forcolonoscopic surveillance, for the management ofmetabolic bone disease, and for the care of childrenwith inflammatory bowel disease.

< Use of the BSG discussion forum available on the BSGwebsite to enable ongoing feedback on the publisheddocument http://www.bsg.org.uk/forum (accessedOct 2010).The present document is intended primarily for the

use of clinicians in the United Kingdom, and serves toreplace the previous BSG guidelines in IBD, whilecomplementing recent consensus statements publishedby the European Crohn’s and Colitis Organisation (ECCO)https://www.ecco-ibd.eu/index.php (accessed Oct2010).

1.0 INTRODUCTIONThese guidelines have been commissioned by theClinical Services and Standards Committee of theBritish Society of Gastroenterology (BSG) forclinicians and allied professionals caring for patients

with inflammatory bowel disease in the UnitedKingdom. The authors of these guidelines weremembers of the BSG IBD Committee at the time.This committee is elected by fellow members of theIBD section of the Society. They replace the guide-lines published in 2004 by Carter et al.1 They havebeen written with close reference to the recentEuropean evidence-based consensus documents onCrohn’s disease2e4 and ulcerative colitis5e7

produced by the European Crohn’s and ColitisOrganisation (ECCO) (https://www.ecco-ibd.eu/index.php (accessed Oct 2010)). Although theseconsensus documents provide a comprehensive andauthoritative review of the evidence base underlyingdefinitions, diagnosis and current management webelieve there are still compelling reasons to issuea set of up-to-date guidelines for UK practice:1. These diseases are complex and recent UK-wide

audits have demonstrated wide variation inclinical practice.8 9

2. There may be important differences betweenguidelines and consensus. Clinical practiceguidelines are ‘systematically developed state-ments to assist practitioner and patient deci-sions about appropriate healthcare for specificclinical circumstances’. Their specific purpose isto make explicit recommendations with anintent to influence what clinicans do.10 Recom-mendations for practice with particular refer-ence to one country may not always be identicalto consensus statements (eg, use of maintenanceanti-tumour necrosis factor (TNF) antibodies inCrohn’s disease).

3. The recent publication of a set of UK ServiceStandards for the healthcare of people who haveIBD is very relevant to guidelines for UKpractice. http://www.ibdstandards.org.uk(accessed Oct 2010).11

4. UK practice is influenced by guidance from theNational Institute for Clinical Excellence (NICE)http://www.nice.org.uk/ (accessed Oct 2010).

5. In some areas, the approach of UK physiciansdiffers from the European consensus, and indeedfrom North American practice, and the presentdocument provides an appropriate and necessaryaddition to the current literature. This isparticular necessary at the present time, whennew therapies are being introduced in IBD, andpreviously accepted management paradigms arebeing extensively revised.

6. Publication of these guidelines will be supportedby the establishment of a discussion forum on the

1Gastrointestinal Unit, NinewellsHospital, Dundee, UK2Derby Digestive DiseaseCentre, Royal Derby Hospital,Derby, UK3Department of Surgery,University College LondonHospitals, UK4Department ofGastroenterology, Royal Devon& Exeter Hospital, UK5Gastrointestinal Unit, WesternGeneral Hospital, Edinburgh, UK6Crohn’s and Colitis UK (NACC),St. Albans, UK7Department of Paediatrics, StGeorge’s Hospital, London, UK8Department ofGastroenterology, St. Mary’sHospital, London, UK9Department Gastroenterology,University Hospital of NorthTees, UK10Endoscopy Unit, Royal LondonHospital, UK11Department ofGastroenterology, UniversityCollege London Hospitals, UK

Correspondence toDr Craig Mowat,Gastrointestinal Unit, NinewellsHospital & Medical School,Dundee DD1 9SY, UK;[email protected]

Revised 22 November 2010Accepted 7 December 2010

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BSG website to enable ongoing feedback on the publisheddocument http://www.bsg.org.uk/forum (accessed Oct 2010).

1.1 Guideline developmentThe guidelines were drafted shortly after the ECCO consensuswas published in the knowledge of the extremely rigorousnature and literature review accompanying that process;throughout the current document, reference is made to theECCO consensus statements. Each author responsible fordrafting sections carried out a further literature review and thedraft and accompanying evidence base was extensively discussedin committee.

The ECCO recommendations were formally compared to the2004 BSG guidance at the outset, in order to identify areas ofdisparity in opinion and content. The important issue ofassessing guideline quality has been addressed by use of theAGREE tool (see section 1.2). We feel readers will want to assessthe recommendations as they would for other guidelines,including a judgement based on accompanying levels ofevidence, which are included throughout the text.

A preliminary document was drafted by contributing authors(coordinated by CM). Recommendations were submitted bycontributing authors and voted on before being incorporatedinto the guidelines.

Draft guidelines were submitted for review by the BSGClinical Services and Standards Committee before beingsubmitted for further review by BSG council members andsimultaneously by external reviewers chosen by the editor ofGut.

The format of the first edition of the guidelines has largelybeen retained with modifications to emphasise aspects of servicedelivery and patient expectations relevant to UK practice.Sections have been added on UK standards of care and principlesof nutrition. Drug therapies have been given a separate sectionrather than being included in disease management and guide-lines have been extensively re-written to take account ofdevelopments in use of immunosuppressive and biologicaltreatments.

1.2 Assessing the quality of guidelines: The AGREE instrumentThere have been attempts to develop external validation forclinical practice guidelines; the best characterised of these is theAGREE instrument developed by the AGREE collaboration(http://www.agreecollaboration.org/intro/ (accessed Oct 2010)).The audit department of the Royal College of Physicians hasadopted this tool. It identifies six criteria of quality which areaddressed here.

1. Scope and purposeThe guidelines are intended for use by clinicians and otherhealthcare professionals in managing patients with ulcerativecolitis and Crohn’s disease in the light of recent guidancepublished by NICE and the development of the IBD standards ofcare. They are primarily aimed at management of adult patients:there are separate guidelines published for the care of childrenwith IBD (http://bspghan.org.uk/IBDGuidelines (accessed Oct2010)). They contain reference to specific issues relating tomanagement of adolescents with IBD.

2. Guideline development group membership and stakeholderinvolvementMembership of the group is detailed at the end of the document:it includes medical and surgical gastroenterologists, IBDspecialist nurses, members of the British Dietetic Association,

and patient representative groups. The section on imaging hasbeen approved by the British Society of Gastrointestinal andAbdominal Radiology committee.

3. Rigour of developmentThe published literature has been searched using Pubmed,Medline and the Cochrane database. The guidelines relyconsiderably on consensus statements published by the Euro-pean Crohn’s and Colitis Organisation (ECCO).2e7 In order toharmonise management guidelines with the ECCO consensusstatements, we have adopted a similar style of gradedrecommendations (graded AeD), determined by the level ofsupporting evidence (graded level 1e5) as described by theOxford Centre For Evidence Based Medicine (table 1). Areas ofdisagreement about the recommendation grade were subjectedto discussion and if necessary voting by members of the guide-lines group. Where possible, the health benefits, side effects andrisks of recommendations have been discussed. The guidelineshave been peer reviewed according to the editorial policy of Gut.

4. Clarity and presentationRecommendations are intended to be specific to particularsituations and patient groups; where necessary, different optionsare listed. Key recommendations are linked to discussion threadson a discussion forum hosted on the BSG website.

5. ApplicabilityWhere necessary, we have discussed organisational changes thatmay be needed in order to apply recommendations. We haveattempted to identify key criteria for monitoring and auditpurposes.

6. Editorial independence and conflict of interestGuideline group members have declared any conflicts of interest.

1.3 Scheduled review of guidelinesThe content and evidence base for these guidelines should berevised within 4 years of publication, to take account of newevidence. We anticipate the guidelines will continue to evolvethrough evidence gathered by regular national audit of IBDstandards and services. Guidelines, by their nature, will becomeoutdated as new evidence is published. With this in mind (andalso to provide user feedback) links to the BSG discussion forumrelating to specific sections of these guidelines are included inthis document. These forums are accessible to any member ofthe BSG who are encouraged to contribute citing the appropriatenew evidence. In line with the agree tool the BSG forum willalso provide some user feedback on the guidelines. The links willbe at http://www.bsg.org.uk/forum/ and the links for specificsections are also imbedded within this document.

2.0 SERVICE DELIVERY2.1 Impact of inflammatory bowel disease on patients andsocietyWith a reported prevalence of 400 per 100 00012 there areapproximately 240 000 patients with IBD in the UK (ulcerativecolitis: 243/100 000¼146 000 people in UK population of 60million; Crohn’s disease: 145/100 000¼87 000 people in UK).The incidence of Crohn’s disease in the UK increased markedlybetween the 1950s and the 1980s.13 14 Since the 1980s theincidence of Crohn’s disease has continued to increase in the UKat a rather slower rate.15 16

Most patients are referred to hospital clinics for evaluation,and approximately 30% of patients are under regular hospitalfollow-up.12 About 2000 people undergo colectomy for IBD each

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year. The lifetime risk for surgery may be as high as 70e80% forCrohn’s disease and 20e30% for ulcerative colitis, depending ondisease severity and location.17e21

Costs of caring for patients with IBD in UK hospitals haverecently been assessed.22 Lifetime costs for IBD are comparableto a number of major diseases, including heart disease andcancer. This implies a substantial burden of disease and disabilitythat is mirrored by the large amount of academic andcommercial activity currently being expended to develop bettertreatments. Patients find symptoms of ulcerative colitis orCrohn’s disease embarrassing and humiliating. IBD can result inloss of education and difficulty in gaining employment orinsurance. It can cause psychological problems and growthfailure or retarded sexual development in young people. Medicaltreatments (steroids, immunosuppressants) can cause secondaryhealth problems, and surgery may result in complications suchas impotence or intestinal failure. The impact of IBD on societyis disproportionately high as presentation often occurs ata young age and has the potential to cause lifelong ill health.

2.2 UK IBD service standardsHistorically, practice guidelines have focused on evidence-basedtherapeutics. This addresses only one aspect of care. Since the2004 BSG guidelines were published, two significant steps havebeen taken to address the quality of care provided to patientswith IBD in the UK.

First, The UK IBD National Audit programme was developedin partnership by the British Society of Gastroenterology, theAssociation of Coloproctology of Great Britain and Ireland,the National Association for Colitis and Crohn’s Disease(NACC) and the Clinical Effectiveness Unit at the RoyalCollege of Physicians, (http://www.rcplondon.ac.uk/resources/inflammatory-bowel-disease-audit (accessed Feb 2011)). Theinaugural audit was performed in 2006. It assessed the structure;organisation, processes and outcomes of care for patients withIBD admitted to UK hospitals and found a wide variation in allaspects across the country. The second round audit in 2008 hasdemonstrated an improvement in many aspects of basic caresuch as the provision of specialist wards, availability of IBDnurses, the prescription of prophylactic heparin and the collec-tion of stool specimens for culture Clostridium difficile toxin.However, there remains wide variation, with some key deficitsin fundamental aspects of IBD care.

Second, a Working Group of IBD health professionals (chairedby Richard Driscoll, CEO National Association of Colitis andCrohn’s) assembled in 2007 to develop a Statement of Standardsfor IBD Healthcare that could be applied across the UK. Afterwidespread consultation the documentwas published in February2009 and launched in the UK parliaments and legislative assem-blies. It sets out the standards that IBD services should attain, butdoes not prescribe particular models of service organisations. Fullcopies of the IBD Standards document can be downloaded athttp://www.ibdstandards.org.uk (accessed Oct 2010). The Stan-dards of Care are grouped into six areas, addressing all aspectsfromhigh quality clinical care provided by amultidisciplinary IBDteam, through to shared care, patient support and empowerment,education of patients and staff, IT support, along witha commitment to research and service development (see table 2).Importantly, the Standardswill be assessed in future rounds of theNational Audit programme. Furthermore, in England theHealthcare Commission has already adopted several key elementsin to the Annual Health Check, to cross-check Hospital Trusts’declarations against Core Standards. IBD Service improvementtools can be found at http://www.ibdstandards.org.uk.

2.3 Sources of patient education and supportWritten information about IBD should be provided in outpatientclinics, ward, and endoscopy areas (IBD Standard D1). Patientsbeing considered for surgery should be offered information abouttheir operation, and where possible, the option of talking topatients who have had pouch surgery or a permanent ileostomy.Patients should be offered advice on where additional informa-tion may be obtained and help in interpreting informationwhere the need arises. Sources are too many to providea comprehensive list. The following provide access to bothgeneral and more detailed information:< Crohn’s and Colitis UK: http://www.nacc.org.uk< The Crohn’s and Colitis Foundation of America. http://

www.ccfa.org< CORE (Digestive Disorders Foundation): http://www.core-

charity.org.uk< British Society of Gastroenterology: http://www.bsg.org.uk< NHS Choices: https://www.nhs.uk (accessed Oct 2010).< NHS Evidence: http://www.evidence.nhs.uk< UK Clinical Research Network portfolio (gastrointestinal):

http://public.ukcrn.org.uk (accessed Oct 2010).

Table 1 Evidence levels (EL) and recommendation grades (RG) (adapted from the Oxford Centre for Evidence Based Medicine,http://www.cebm.net/index.aspx?o¼1025 (accessed Oct 2010))

EL Individual study Technique

1a Systematic review (SR) with homogeneity of level 1 diagnostic studies Systematic review (SR) with homogeneity of randomised controlled trials (RCTs)

1b Validating cohort studies with good reference standards Individual RCT (with narrow CI)

1c Specificity is so high that a positive result rules in the diagnosis (SpPIn)or sensitivity is so high that a negative result rules out the diagnosis (SnNout)

All or none

2a SR with homogeneity of >level 2 diagnostic studies SR (with homogeneity) of cohort studies

2b Exploratory cohort study with good reference standards Individual cohort study (including low quality RCT; eg, <80% follow-up)

2c ’Outcomes’ research; ecological studies

3a SR with homogeneity of 3b and better studies SR with homogeneity of case-control studies

3b Non-consecutive study; or without consistently applied reference standards Individual caseecontrol study

4 Caseecontrol study, poor or non-independent reference standard Case series (and poor quality cohort and caseecontrol studies)

5 Expert opinion without explicit critical appraisal, or based on physiology,’bench research’ or ’first principles’

Expert opinion without explicit critical appraisal, or based on physiology,’bench research’ or ’first principles’

RG GRADES OF EVIDENCE

A Consistent level 1 studies

B Consistent level 2 or 3 studies or extrapolation from level 1 studies

C Level 4 studies or extrapolation from level 2 or 3 studies

D Level 5 evidence or troublingly inconsistent or inconclusive studies of any level

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< CICRA (Crohn’s in Childhood Research Association): http://www.cicra.org/

Recommendation for service delivery< Hospitals involved in the care of patients with IBD should

model their service as far as possible to meet the IBD ServiceStandards (EL5, RG D).

IBD Service Standards (service delivery):It is suggested that an IBD service is delivered within thefollowing basic framework:< The IBD team

– Patients with IBD should be cared for by a defined IBD teamwith named personnel comprising gastroenterologists,colorectal surgeons, clinical nurse specialists, a dietician,pharmacist, pathologist and GI radiologist (IBD StandardA1). The roles and responsibilities of an IBD nurse specialistare outlined within Royal College of Nursing guidance,(http://www.rcn.org.uk/__data/assets/pdf_file/0007/107746/003194.pdf (last accessed Oct 2010)). The IBD team shouldhave access to the following essential supporting services:a psychologist/counsellor, rheumatologist, ophthalmologist,dermatologist, obstetrician, nutrition support team, a paedi-atric gastroenterology clinical network, general practise(IBD Standard A2).

< Multi-disciplinary care (IBD Standard A3)– The IBD team should have regular meetings to discusspatients with complex needs

– Patients should have access to a joint or parallel gastro-enterologyesurgical clinic that is held at least monthly in aunit that meets the standards set out in this document.

< Patient management (IBD Standard A4)– Local protocols should be developed to facilitate referral ofsymptomatic patients in whom IBD is suspected.

– All patients with IBD who are admitted to hospital shouldbe notified to the IBD specialist nurse (IBD Standard A10).

– Newly diagnosed patients for whom surgery is not animmediate consideration should be transferred to the careof the medical gastroenterology team.

– IBD inpatients should, wherever possible, be cared for ina specialist ward area with 24 h access to intensive carefacilities on site.

– IBD surgery should be undertaken by recognised colorectalsurgeons, who are core members of the IBD team, or theirsupervised trainees, in a unit performing such operationsregularly (IBD Standard A7).

– All IBD outpatients should have an annual review and basicinformation recorded. This may be in a hospital/commu-nity clinic, or by telephone follow-up, and should be doneby a healthcare professional with recognised competence inIBD (Standard A11).

– Patients with IBD should have access to a dedicatedtelephone service supported by an answer-phone, whichcan provide a response by the end of the next working day(Standard A11).

– Patients experiencing a possible relapse of their IBD shouldhave access to specialist review within a maximum of fiveworking days (Standard A11).

– There must be a defined policy and protocol for transitionalcare of adolescents with IBD (Standard A12).

3.0 INFLAMMATORY BOWEL DISEASE3.1 DefinitionsThe definitions and diagnosis of ulcerative colitis and Crohn’sdisease are thoroughly reviewed in the ECCO consensus docu-ments.2 6 In particular, the definitions of ulcerative colitis andCrohn’s disease acknowledge the revised Montreal classification

Table 2 IBD service standards

Standard Implementation standard

A: High-quality clinical care

A1 The IBD team*

A2 Essential supporting services*

A3 Multi-disciplinary working*

A4 Referral of suspected patients with IBD

A5 Access to nutritional support and therapy*

A6 Arrangements for use of immunosuppressive and biological therapies

A7 Surgery for IBD*

A8 Inpatient facilities*

A9 Access to diagnostic services

A10 Inpatient care*

A11 Outpatient care*

A12 Arrangements for the care of children and young people who have IBD

B: Local delivery of care

B1 Arrangements for shared care*

C: Maintaining a patient-centred service

C1 Information on the IBD service*

C2 Rapid access to specialist advice*

C3 Supporting patients to exercise choice between treatments

C4 Supporting patients to exercise choice between care strategies foroutpatient management

C5 Involvement of patients in service improvement*

D: Patient education and support

D1 Provision of information*

D2 Education for patients

D3 Information about patient organisations

D4 Support for patient organisations

E: Information technology and audit

E1 Register of patients under the care of the IBD service

E2 Developing an IBD database

E3 Participation in audit

F: Evidence-based practice and research

F1 Training and education

F2 Research

F3 Service development

*Adopted by Healthcare Commission.IBD, inflammatory bowel disease.

Table 3 Definition of ulcerative colitis phenotypeaccording to the Montreal classification23

Maximal extent of inflammationobserved at colonoscopy

Proctitis E1

Left-sided e extending up to splenic flexure E2

More extensive disease E3

Table 4 Definition of Crohn’s disease phenotype according to theMontreal classification23

Age of onset Location Behaviour

#16 years (A1) Ileal (L1) Non-stricturing,

Non-penetrating (B1)

17�40 years (A2) Colonic (L2) Stricturing (B2)

>40 years (A3) Ileo-colonic (L3) Penetrating (B3)

*Isolated upper GI disease (L4) + ‘p’ if peri-anal disease

*L4 is a modifier that can be added to L1 e 3 when concomitant upper gastrointestinal (GI)disease is present.

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which attempts to more accurately characterise the clinicalpatterns of IBD.23 24

Ulcerative colitis is characterised by diffuse mucosal inflam-mation limited to the colon. It is classified according to themaximal extent of inflammation observed at colonoscopybecause this is most clearly related to the risk of complications,including dilatation and cancer. The implications of limitedmacroscopic disease with extensive microscopic inflammationremain unclear.

Crohn’s disease is characterised by patchy, transmuralinflammation, which may affect any part of the gastrointestinaltract. It may be defined by: age of onset, location, or behaviour.

About 5% of patients with IBD affecting the colon areunclassifiable after considering clinical, radiological, endoscopicand pathological criteria, because they have some features of bothconditions. This is now termed as ‘IBD, type unclassified (IBDU)’.The term ‘indeterminate colitis (IC)’ should be reserved for caseswhere colectomy has been performed and the pathologistremains unable to classify the disease after a full examination.23

If all patients are characterised in this standard fashion, thisshould facilitate data collection for an IBD registry and clinicalresearch.

3.2 Clinical features and course of disease17e19 21 25e27

Ulcerative colitisThe cardinal symptom of ulcerative colitis is bloody diarrhoea.Associated symptoms of colicky abdominal pain, urgency, ortenesmus may be present. It is a severe disease that used tocarry a high mortality and major morbidity. With modernmedical and surgical management, the disease now has a slightexcess of mortality in the first 2 years after diagnosis, but littlesubsequent difference from the normal population. However,severe colitis is still a potentially life-threatening illness. Theclinical course is marked by exacerbation and remission. About50% of patients have a relapse in any year. An appreciableminority has frequently relapsing or chronic, continuous diseaseand overall, 20e30% of patients with pancolitis come tocolectomy. After the first year approximately 90% of patientsare fully capable of work (defined by <1 month off work/year),although significant employment problems remain an issue fora minority.

Crohn’s diseaseSymptoms of Crohn’s disease are more heterogeneous, buttypically include abdominal pain, diarrhoea and weight loss.Systemic symptoms of malaise, anorexia, or fever are morecommon. Crohn’s disease may cause intestinal obstruction dueto strictures, fistulae (often perianal) or abscesses. Surgery is notcurative and management is directed to minimising the impactof disease. At least 50% of patients may require surgical treat-ment in the first 10 years of disease and approximately 70e80%may require surgery within their lifetime, dependent on the siteof the disease. The overall mortality is slightly higher than thenormal population and is greatest in the 2 years after diagnosisor in those with upper gastrointestinal disease. The clinicalcourse is also characterised by exacerbations and remission.Crohn’s disease tends to cause greater disability than ulcerativecolitis with only 75% of patients fully capable of work in theyear after diagnosis and 15% of patients unable to work after5e10 years of disease.

Both ulcerative colitis and Crohn’s colitis are associated withan equivalent increased risk of colonic carcinoma.28e31 Smokingincreases the risk of Crohn’s disease, but decreases the risk ofulcerative colitis through unknown mechanisms.32

3.3 Diagnosis and investigation2 6 33

The diagnosis of IBD is confirmed by clinical evaluation anda combination of haematological, endoscopic, histological, orimaging-based investigations. In the case of ulcerative colitis thediagnosis should be made on the basis of clinical suspicionsupported by appropriate macroscopic findings on sigmoidos-copy or colonoscopy, typical histological findings on biopsy andnegative stool examinations for infectious agents. For Crohn’sdisease the diagnosis depends on demonstrating focal, asym-metric and often granulomatous inflammation but the investi-gations selected vary according to the presenting manifestations,physical findings and complications. For all patients, thereshould be local referral patterns agreed so that patientssuspected of having IBD can be referred for rapid consultationand assessment.

3.3.1 History and examinationA full history should include recent travel, medication (includingantibiotics and non-steroidal anti-inflammatory drugs), sexualand vaccination history where relevant. Particular attentionshould be paid to established risk factors including smoking,family history, previous appendicectomy and recent episodes ofinfectious gastroenteritis. Details should include the stoolfrequency and consistency, urgency, rectal bleeding, abdominalpain, malaise, fever, weight loss and symptoms of extra-intes-tinal (joint, cutaneous and eye) manifestations of IBD. Exami-nation should include general well-being, measurement ofweight, calculation of body mass index, pulse rate, bloodpressure, temperature, check for anaemia, fluid depletion,abdominal tenderness or distension, palpable masses andperineal examination.

3.3.2 Initial investigationsLaboratory investigations should include full blood count, ureaand electrolytes, liver function tests and erythrocyte sedimenta-tion rate or C reactive protein, ferritin, transferrin saturation,vitamin B12 and folate. Serological markers such as pANCA,ASCA are present in a significant proportion of patients with IBDbut there is no evidence base to recommend their use in thediagnosis of IBD. Faecal calprotectin is accurate in detectingcolonic inflammation and can help identify functional diarrhoea.Microbiological testing for Clostridium difficile toxin, in addition tostandard organisms, is increasingly important. C difficile infectionhas a higher prevalence in patients with IBD through unknownmechanisms, may not be confined to the colon, and is associatedwith increased mortality. A minimum of four stool samples isrequired to detect 90% of cases.34 35 Cytomegalovirus (CMV)should be considered in severe or refractory colitis, as reactivationis common in patients with IBD on immunosuppression. Addi-tional tests may be needed for patients who have travelled abroad.Abdominal radiography is essential in the initial assessment ofpatients with suspected severe IBD: it excludes colonic dilatationand may help assess disease extent in ulcerative colitis or identifyproximal constipation. In Crohn’s disease abdominal radiographymay give an impression of a mass in the right iliac fossa, or showevidence of small bowel dilatation.

3.3.3 EndoscopyColonoscopy with multiple biopsies (at least two biopsies fromfive sites including the distal ileum and rectum) is the first lineprocedure for diagnosing colitis. It allows classification of diseasebased on endoscopic extent, severity of mucosal disease andhistological features. It also allows assessment of suspectedstenoses in the distal ileum or colon.

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In acute severe colitis, full colonoscopy is rarely needed36 andmay be contraindicated. Phosphate enema prior to sigmoidos-copy is considered safe in acute severe colitis, except in thosewith colonic dilatation. A rectal biopsy is best taken forhistology even if there are no macroscopic changes. Uppergastrointestinal (GI) endoscopy should be considered in coex-isting dyspepsia. The role of small bowel endoscopy (entero-scopy/capsule) has yet to be defined. The available evidence issummarised in a consensus statement produced by OMED/ECCO.37

3.4 HistopathologyHistopathological examination of biopsy specimens should becarried out according to the BSG guideline, ‘A StructuredApproach to Colorectal Biopsy Assessment’.38 There should bean attempt to define the type of IBD, to mention other coexis-tent diagnoses or complications and to mention the absence orpresence of any dysplasia and its grade. The appropriate term forIBD that cannot be classified is ‘IBD Unclassified’.23 Medical andsurgical therapy may modify the histological appearances of IBDand these should be taken into account when assessing IBDbiopsy pathology.2 39

3.5 Imaging modalitiesImaging can be helpful in diagnosis, assessment of disease extentand severity and for investigation of suspected complications.Each modality has its own advantages and drawbacks and thetests are often complimentary. It is desirable for clinicians todiscuss imaging with a radiologist to avoid unnecessary exposureto ionising radiation (see table 5).40 41

3.5.1 UltrasoundUltrasound cannot comprehensively assess the gut when used inisolation. It is the first-line test for gallstones and kidney stones,which should not be forgotten as complications of Crohn’sdisease. In expert hands it has a high sensitivity for detectingdisease, particularly in the terminal ileum. However, suchexpertise is not widely available in the UK. Doppler techniquesare useful in the assessing the degree of disease activity. It hasreasonable sensitivity for documenting the presence of compli-cating abscess, particularly in thinner patients and is a usefulfirst line test in this context.42 43 Importantly, there is no radi-ation dosage or contrast agent needed and it is safe in pregnancy.

3.5.2 Magnetic resonance imagingModern MRI hardware and software facilitate rapid and accu-rate assessment of the small bowel. Importantly, there is noradiation dosage which makes the technique ideally suited to theCrohn’s disease population given their age demographic andneed for repeat imaging. Employed sequences are complimentaryin characterising the bowel wall in Crohn’s disease (eg, docu-menting the presence of mural oedema or abnormal gadolinium

enhancement patterns). Large comparative trials with conven-tional fluoroscopic barium techniques are currently lacking butrecent data (mainly single-site studies) suggest MRI is equiva-lent or superior, particularly in those with established disease.Early mucosal disease such as aphthous ulceration is better seenby wireless capsule endoscopy or high-quality fluoroscopicstudies.44 45 MRI provides information about disease activityand may be useful in distinguishing between inflammatory andfibrotic stricturing. It also has very high sensitivity for detectionof extraluminal complications (including abscess formation) anddemonstrates internal fistulisation with good accuracy. PelvicMRI has a particular place in the evaluation of perianal disease,and provides a complementary mode of assessment to endo-analultrasound and examination under anaesthetic. MR enter-ography is more widely performed in the UK than MR enter-oclysis. Availability of small bowel MRI (both equipment andexpertise) is currently limited to around 40% of UK institutions.Magnetic resonance cholangiopancreatography is the initialinvestigation of choice in suspected sclerosing cholangitis.

3.5.3 Computed tomography scanningCT imaging of the bowel (either CT enteroclysis or CT enter-ography) provides similar information to MRI, although tissuecharacterisation capability is less. It is traditionally the ‘goldstandard’ for the detection of extraluminal complications, notablyabscess formation. Intravenous contrast administration is usuallyperformed during CT. Advantages over MRI include widespreadavailability, rapid image acquisition (few seconds) and superiorspatial resolution. However CT imparts a significant radiationburden, which may carry a cancer risk.41 Furthermore radiationcumulative doses may be significant with repeat imaging.46

Provision of CT enterography/enteroclysis is currently similar toMRI in the UK. Unprepared CT (ie, without bowel distension)has an important role in rapidly and accurately assessing patientsfor acute complications such as obstruction or sepsis. ImportantlyCT is usually available out of hours.

3.5.4 Barium fluoroscopyHigh-quality barium studies have superior sensitivity over cross-sectional techniques for subtle early mucosal disease, althoughin those with established and/or more advanced disease, bothCTand MR may be equivalent and also provide information onsubmucosal disease. Barium fluoroscopy imparts a radiation doseto patients (approximately one third to one half of the CT dose)with its associated risks. This risk may be of particular impor-tance to young patients with IBD requiring immunosuppressivetherapies.

3.5.5 Isotope-labelled scansA variety of nuclear medical techniques can be used in theassessment of IBD, although they have no role in the primarydiagnosis of IBD.47 Technetium-99m labelling of white bloodcells remain a widely acceptable scintigraphic method for theevaluation of disease extension and severity. Positron emissiontomography alone or with CT using fluorine-18 fluorodeox-yglucose appears to be a promising method of measuringinflammation in patients with IBD. These techniques might beconsidered when colonoscopy is not completed successfully orother imaging modalities are negative.

3.5.6 Imaging common clinical scenarios

Suspected severe IBDThe plain abdominal x-ray is essential in the initial assessmentof patients with suspected severe IBD: it excludes colonic

Table 5 Dosage and risk associated with diagnostic x-ray procedures,www.hpa.org.uk (accessed Oct 2010)

Diagnostic x-rayprocedure

Typical effectivedoses (mSv)

Lifetime additional risk offatal cancer per examination

Chest 0.02 1 in 1 000 000

Pelvis 0.7 1 in 30 000

Abdomen 0.7 1 in 30 000

Barium follow-through 3 1 in 6700

Barium enema 7 1 in 3000

CT abdomen/pelvis 10 1 in 2000

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dilatation and may help assess disease extent in ulcerative colitisor identify proximal constipation. In Crohn’s disease abdominalradiography may give an impression of a mass in the right iliacfossa, or show evidence of small bowel dilatation.

Assessing the small bowel in Crohn’s diseaseMRI, CT, ultrasound and barium fluoroscopy all have estab-lished roles in defining disease extent in those with knowndisease. The role of small bowel endoscopy (enteroscopy/capsule) has yet to be defined. The available evidence issummarised in a consensus statement produced by OMED/ECCO.37 Choice depends on local availability and expertise aswell as patient factors and clinical indication. However, when-ever possible, those techniques not imparting radiation shouldbe employed. Small studies in expert centres have suggestedMRI and CT have the better diagnostic yield partly because ofthe detection of extra mucosal disease.45 48 49

Imaging and anti-TNF therapy in Crohn’s diseaseBefore using anti-TNF therapy it is important to excludeun-drained abscess collections where these may be present. Thisis particularly true in fistulising disease. Cross-sectional tech-niques including ultrasound, MRI or CT should be employed.CT and MRI are overall more sensitive than ultrasound. MRImay be used to monitor response of fistulising perianal disease.

Recommendations< All patients with diarrhoea should have stools sampled for

culture and C difficile toxin. Four samples are required for 90%sensitivity. (EL4, RGC).

< Imaging techniques may be constrained by availability andlocal expertise. In general, attempts should be made tominimise exposure to ionising radiation.

< For imaging the small bowel, MRI is the preferred techniquewhere available (EL 2b).

< All new patients should have their disease phenotypeclassified in accordance with the Montreal Classification(EL 5, RG D).

IBD Service Standards for diagnosis and investigation: (IBDstandard A)< Local guidelines/referral pathways should be in place for rapid

referral of new/suspected cases of IBD.< The patient’s weight and body mass index (BMI) should be

measured at each attendance.< Outpatients should wait no more than 4 weeks for radiological/

endoscopic investigations.< Inpatients with severe disease should wait no more than 24 h

for necessary imaging or endoscopy.< Processing of biopsies should be rapid (2e5 days maximum

according to need).

4.0 THERAPEUTIC OPTIONS IN THE MANAGEMENT OF IBDhttp://www.bsg.org.uk/forum (accessed Oct 2010)/(Thissection examines data on efficacy: specific recommendations areincluded in sections 5, 6, and 7).

4.1 NutritionMalnutrition in IBD is common and multi-factorial in origin.Nutritional assessment, including BMI is important: there arevalidated tools such as Malnutrition Universal Screening Tool(MUST) to guide assessment,50 (http://www.bapen.org.uk/musttoolkit.html (last accessed Oct 2010)). Patients with activecolitis may have secondary lactose intolerance and a dairy freediet may reduce gas and bloating (EL5, RGD).

4.1.1 Nutritional support,(http://www.nice.org.uk/nicemedia/pdf/cg032fullguideline.pdf(last accessed Oct 2010))MicronutrientsSpecific attention should be paid to nutrient deficits such ascalcium, vitamin D, other fat soluble vitamins, zinc, iron and(after ileal resection especially) vitamin B12 status. Serumvitamin B12 is best measured annually in patients with ilealCrohn’s disease.51

MacronutrientsIn specific circumstances, protein and caloric support is indicated,such aswhen the absorptive capacity of the gut is reduced in shortbowel syndrome or in the perioperative care of patients withsignificant (more than 15%) weight loss or low BMI.52 This maymean total parenteral nutrition (TPN) including home TPN ina minority of Crohn’s disease patients with intestinal failure.Approximately 20% of the home TPN patients in Europe haveunderlying Crohn’s disease that is about one case per 1.5million population.53 See BSG guidelines on short bowelsyndrome,54 (http://www.bsg.org.uk/clinical-guidelines/small-bowel-nutrition/guidelines-for-management-of-patients-with-a-short-bowel.html (last accessed Oct 2010)).

4.1.2 Nutritional therapy55

Therapeutic liquid feedsThere is no indication for liquid feed to treat ulcerative colitis.Enteral nutritional therapy alters the inflammatory response inCrohn’s disease and may be useful in therapy.56 57 In Crohn’sdisease, exclusive enteral nutrition (EEN), usually given for3e6 weeks, is an alternative therapy to corticosteroids for activeCrohn’s disease. There is no difference in efficacy betweenelemental and polymeric diets when used to induce remission inCrohn’s disease.58 When used in children EEN is effective atinducing remission for small and large bowel disease in 60e80%.However, in adults liquid feeds appear less effective than corti-costeroids in controlled studies (EL2b) although this may relateto tolerability. The efficacy of EEN to treat active Crohn’sdisease has not been assessed in controlled studies againstnormal diet. There is little evidence to support the use of liquidfeeds as maintenance therapy for Crohn’s disease.59

Advantages of exclusive enteral nutritionLiquid feeding as an alternative to steroids may avoid adverseeffects of steroids and ensure optimal growth before fusion ofepiphyses prohibits further growth.58 60 Against this is the issueof tolerability in adults of feeds taken orally.

PrebioticsPrebiotics are non-digestible dietary carbohydrates,such asfructo-oligosaccharides which are fermented by the gut micro-flora to produce short-chain fatty acids. Their role is unproven todate.61

ProbioticsBacteria or yeast generally ingested orally as therapy are termedprobiotics. They may be administered as a single organism ora defined mixture, aiming to beneficially alter the microbialecology of the gut. The agents most studied in IBD are E coliNissle 1917, VSL#3, Lactobacillus rhamnosius GC, Bifidobacteriumand Saccharomyces boulardii.62

There is evidence for the effectiveness of VSL#3 in preventingpouchitis63 64 (see section 5.7) and some evidence of benefit inmaintenance and treatment of ulcerative colitis.65 66

Three randomised placebo-controlled studies have shown thatE coli Nissle 1917 (Mutaflor�) 200 mg daily is equivalent to

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standard doses of mesalazine in maintaining remission in ulcer-ative colitis67 (EL 1b, RG A), and therefore may be an option forpatients who are unable or unwilling to take mesalazine.

There is no clear evidence to support any role of probiotics inthe maintenance of Crohn’s disease either after surgical ormedically induced remission.68

Total parenteral nutrition with ‘bowel rest’69e72

There is no good evidence to support the use of parenteralnutrition as an adjunct or sole therapy to induce remission inCrohn’s disease or ulcerative colitis.

4.2 Smoking cessation32 73e78

Smoking is an important environmental factor in the pathogen-esis of IBD, though the mechanisms remain under investigation.Current smokers are more likely to develop Crohn’s disease and,following diagnosis, have a poorer prognosis with a significantlyhigher chance of surgical resection, and (if smoking stillcontinues) a greater chance of recurrence at the surgical anasto-mosis. Smoking cessation is associated with a 65% reduction inthe risk of a relapse as compared with continued smokers,a similar magnitude to that obtained with immunosuppressivetherapy.79

4.3 Non-steroidal anti-inflammatory drugsThere are many publications claiming an adverse effect ofnon-steroidal anti-inflammatory drugs (NSAIDs) in precipiatingde novo IBD or exacerbating pre-existing disease, although theevidence remains contradictory and confusing. The currentposition is summarised in a recent review.80 There is someevidence that mucosal damage is mediated by dual inhibition ofCOX-1 and COX-2. Selective inhibition with COX-2 inhibitorsor COX-1 inhibition with low dose aspirin seems to be safe, atleast in the short term.81

4.4 Drugs used in the treatment of inflammatory bowel diseaseTherapy for IBD is a rapidly evolving field, with many newbiological agents under investigation that are likely to changetherapeutic strategies radically in the next decade. Details of theprincipal drugs can only be summarised in this document.Patient information sheets can be downloaded from: http://www.bsg.org.uk/patients/general/patient-information.html(last accessed Oct 2010).

4.4.1 Aminosalicylates82

5-Aminosalicylic acid (5-ASA) or mesalazine (‘mesalamine’ inthe USA) can be delivered in millimolar concentrations to thegut lumen by a variety of oral tablets, sachets or suspensionsusing pH-dependent release mechanisms, multimatrix deliverysystems, or conjugation via a diazo bond to a variety of carriermolecules with release of 5-ASA after splitting by bacterialenzymes in the large intestine. They can also be used as topicalagents in the form of liquid or foam enemas, or suppositories.They act on epithelial cells by a variety of mechanisms tomoderate the release of lipid mediators, inflammatory cells,cytokines and reactive oxygen species.

Oral forms include:e pH-dependent release/resin coated (Asacol�, Salofalk�,Ipocol�, Mesren�)e time-controlled release (Pentasa�)eMultimatrix delivery systems (Mezavant XL�)e delivery by carrier molecules, with release of 5-ASA aftersplitting by bacterial enzymes in the large intestine (sulfasala-zine (Salazopyrin�), olsalazine (Dipentum�), balsalazide(Colazide�)).

Efficacy in ulcerative colitis83 84

For ulcerative colitis, greater clinical improvement (but notnecessarily remission) is associated with doses >3 g/day. Clinicalimprovement characteristically occurs at twice the remissionrate. In a meta-analysis of oral 5-ASA for active ulcerative colitis,of 19 trials involving 2032 patients, nine were placebo controlledand 10 compared mesalazine with sulfasalazine. The outcome ofinterest on an intention-to-treat principle was the failure toinduce remission, so that a pooled OR <1.0 indicates onetreatment to be more effective than another. Mesalazine wasmore than twice as effective as placebo (OR 0.39; CI 0.29 to0.52, but not significantly better than sulfasalazine (OR 0.87; CI0.63 to 1.20). More recent trials have studied the efficacy of highdose 5-ASA in ulcerative colitis. The rate of remission at the endof these studies is similar on 2.4 g and 4.8 g daily. However, thereappeared to be faster resolution of symptoms on 4.8 g dailycompared to 2.4 g daily.85 86 Increasing colonic concentrations of5-ASA by using a combination of oral and topical preparations ofmesalazine was shown to be more effective than oral therapyalone even in patients with extensive disease.87 Trials in theacute and maintenance phase (see below) suggest that once dailydosing is effective with most preparations of 5-ASA.85 88 Arecent meta-analysis demonstrates that rectal 5-ASA is superiorto rectal steroids for the induction of remission of mild-moderatedistal ulcerative colitis.89

The main role for 5-ASA is maintenance of remission inulcerative colitis. All 5-ASA derivatives show comparable effi-cacy to sulfasalazine, but in a meta-analysis sulfasalazine hada modest therapeutic advantage for maintaining remission (OR1.29, CI 1.08 to 1.57).90 The choice of 5-ASA is debated, but isinfluenced by tolerability (mesalazine is tolerated by 80% ofthose unable to tolerate sulfasalazine), dose schedule (single- ortwice-daily dosing is associated with better compliance) andcost. There is now robust evidence to suggest that single dailydosing is as effective as multiple dosing, and may even besuperior.91 92 Efficacy may depend more on adherence with theprescribed dose than the delivery system. If the delivery systemis considered important, then the drug is best matched to thesite of disease, by using azo-bonded compounds for distaldisease. Maintenance therapy with all 5-ASA drugs may reducethe risk of colorectal cancer by up to 75% (OR 0.25, CI 0.13 to0.48).93 This favours long-term treatment for patients withextensive ulcerative colitis.

Efficacy in Crohn’s disease84

In active Crohn’s ileocolitis, a meta-analysis of the threeplacebo-controlled trials of Pentasa 4 g daily for 16 weeks ina total of 615 patients, showed a mean reduction of the Crohn’sdisease activity index (CDAI) from baseline of e63 points,compared to e45 points for placebo (p¼0.04).94 While thisconfirms that Pentasa 4 g/day is superior to placebo in reducingCDAI, this is unlikely to be of clinical significance. Subgroupanalyses do not provide sufficiently clear answers to whetherone group of patients benefit more than another, and the use ofaminosalicylates as first line therapy in this group is not justifiedby the evidence. The national Cooperative Crohn’s Diseasestudy did identify some benefit in colonic Crohn’s disease fromsulfasalazine at a dose of 4e6 g daily, although this was modest.This effect was not seen with newer preparations of 5-ASA inmore recent studies.95e101

There is no evidence that 5-ASA is superior to placebo for themaintenance of medically induced remission.102 There is evidenceto suggest that mesalazine >2 g/day has a modest effect inreducing relapse after surgery (NNT 10e12), especially after

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small bowel resection (40% reduction at 18 months). Howeverthe cost of therapy and the pill burden for patients are such thatit should probably be reserved for specific patientsdnormallythose with small-bowel disease, and only after more effectivemeasures such as smoking cessation have been instituted.84

Adverse effects of 5-ASA103e105

Side effects of sulfasalazine occur in 10e45% of patients,depending on the dose. Headache, nausea, epigastric pain, diar-rhoea, and oligospermia in men are most common and doserelated. Serious idiosyncratic reactions (including StevenseJohnson syndrome, pancreatitis, agranulocytosis, or alveolitis)are rare. Mesalazine intolerance occurs in up to 15% of patients.Diarrhoea (3%), headache (2%), nausea (2%) and rash (1%) arereported, but a systematic review has confirmed that all new5-ASA agents are safe, with adverse events that are similar toplacebo for mesalazine or olsalazine. No comparison betweenbalsalazide and placebo has been published, but events werelower than with sulfasalazine. Acute intolerance to all 5-ASAs in3% may resemble a flare of colitis since it includes bloody diar-rhoea. Recurrence on rechallenge provides the clue. All amino-salicylates have been associated with nephrotoxicity (includinginterstitial nephritis and nephrotic syndrome), which appearsboth to be idiosyncratic and, in part, dose related.106 Reactionsare rare, but patients with pre-existing renal disease are at higherrisk. A population-based study found the risk (OR 1.60, CI 1.14to 2.26 compared to normal) to be associated with diseaseseverity rather than the dose or type of mesalazine. For patientson maintenance 5-ASA, annual measurement of creatinine issensible, although there is no evidence that monitoring isnecessary or effective at preventing renal impairment. Amino-salicylates should be stopped if renal function deteriorates.

4.4.2 AntibioticsAntibiotics have an important role in treating secondarycomplications in IBD, such as abscess and bacterial over-growth.107 There is some evidence that metronidazole andciprofloxacin have specific uses in Crohn’s disease. There is noclear-cut evidence to support the use of these antibiotics inulcerative colitis as disease modifying therapy.

MetronidazoleMetronidazole in a synthetic nitroimidazole antibiotic andantiprotozoal drug.

Efficacy in Crohn’s disease. Early trials of metronidazole to treatCrohn’s disease showed reductions in blood markers of inflam-mation (ESR and orosomucoid levels).108e110 Following ileo-caecal resection, 20 mg/kg/day for 3 months reduces the risk ofendoscopic recurrence in the short term only.111 (see section6.6.4) Metronidazole is used to treat perianal disease. Theevidence is from case series, it has not been subject to adequatelypowered controlled studies and recent data suggests it is lesseffective than ciprofloxacin.112 Metronidazole treatment ofpouchitis improves diarrhoea without a clear effect on pouchinflammation.113 It appears less effective than ciprofloxacin.

Adverse effects. Metronidazole should be used with caution inthe long term as peripheral neuropathy can occur after a meanduration of 6 months.114

CiprofloxacinThis drug is a fluoroquinolone antibiotic with a broad spectrumof activity against Gram positive and negative bacteria includingmany enteric pathogens.

Efficacy in Crohn’s disease. There are no placebo-controlledstudies of ciprofloxacin to treat active Crohn’s disease thoughcomparisons have been made with other drugs showing similarresponse rates to mesalazine and steroids respectively.115 116

Studies in ulcerative colitis show weak or no effect.117 118 Theevidence suggests a greater benefit than metronidazole inperianal Crohn’s disease and pouchitis.112 119

Adverse effects. Ciprofloxacin is recognised to cause tendonweakness and this effect may be aggravated by steroids.

Antituberculous chemotherapy and other antibiotics in Crohn’sdiseaseThese drugs are not discussed here. The reader is referred to theECCO consensus statement.3

4.4.3 CorticosteroidsCorticosteroids are used in the form of oral prednisolone, pred-nisone, budesonide (among others), or intravenous hydrocorti-sone and methylprednisolone. Topical suppositories, foam orliquid enemas include hydrocortisone, prednisolone meta-sulfobenzoate, betamethasone and budesonide. Many strategiesattempt to maximise topical effects while limiting systemicside-effects of steroids. Budesonide (Entocort�, Budenofalk�) isa poorly absorbed corticosteroid with limited bioavailability andextensive first-pass metabolism that has therapeutic benefitwith reduced systemic toxicity in ileo-caecal Crohn’s disease, orulcerative colitis.120 Beclometasone dipropionate has beenstudied in oral and enema forms in ulcerative colitis, and is nobetter than 5-ASA.121 122

Choice and mechanism123

Corticosteroids are potent anti-inflammatory agents formoderate to severe relapses of both ulcerative colitis and Crohn’sdisease. They have no role in maintenance therapy for eitherdisease. They act through inhibition of several inflammatorypathways: suppressing interleukin transcription, induction ofIkb that stabilises the NFkb complex, suppression of arachidonicacid metabolism and stimulation of apoptosis of lymphocyteswithin the lamina propria of the gut. The anti-inflammatorydose equivalence of prednisolone 5 mg is betamethasone0.75 mg, methylprednisolone 4 mg and hydrocortisone 20 mgthough with differing mineralocorticoid effects (British NationalFormulary, http://bnf.org/bnf/index.htm (accessed Oct 2010)).

Efficacy for active ulcerative colitis124e126

Oral prednisolone (starting at 40 mg daily) induced remission in77% of 118 patients with mild-to-moderate disease within2 weeks, compared to 48% treated with 8 g/day sulfasalazine. Acombination of oral and rectal steroids is better than eitheralone. Adverse events are significantly more frequent at a dose of60 mg/day compared to 40 mg/day, without added benefit, so40 mg appears optimal for outpatient management of acuteulcerative colitis. Too rapid reduction in the dose of steroids canbe associated with early relapse and doses of prednisolone<15 mg day are ineffective for active disease.Budesonide (colonic release preparation) appears as effective

as prednisolone for mildemoderate left-sided and extensivecolitis though in a different formulation to that available forCrohns disease.127

Rectal steroids are effective additional treatments in additionto oral salicylates in mild distal disease, but appear less effectivethan topical aminosalicylates.128 129

Efficacy for active Crohn’s disease95 130e132

Two major trials established corticosteroids as effective therapyfor inducing remission in Crohn’s disease. The National

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Co-operative Crohn’s disease Study randomised 162 patients,achieving 60% remission with 0.5e0.75 mg/kg/day prednisone(the higher dose for more severe disease) and tapering over17 weeks, compared to 30% on placebo (NNT¼3). The compa-rable European Cooperative Crohn’s Disease Study on 105patients achieved 83% remission on prednisone 1 mg/kg/daycompared to 38% on placebo (NNT¼2) over 18 weeks. The highplacebo response rate should be noted, because disease activity inCrohn’s disease (and ulcerative colitis) fluctuates spontaneously.No formal doseeresponse trial has been performed, but 92%remission within 7 weeks was achieved in 142 patients withmoderately active Crohn’s disease given prednisone 1 mg/kg/daywith no tapering. Unfortunately, the majority of patients do notremain in remission following a first dose of steroids; at 1 year,a prolonged steroid response occurs in 44%, with steroiddependency in 36%, and steroid resistance in 20%.133 Budesonideis slightly less effective than prednisolone, but is an appropriatealternative for active ileo-ascending colonic disease. Althoughsteroid therapy provides a symptomatic response in the shortterm and may induce symptomatic remission, this is not typi-cally associated mucosal healing.134 135

Deciding to treat with steroids132

Efficacy should be balanced against side effects, but decisivetreatment of active disease in conjunction with a strategy forcomplete withdrawal of steroids, is often appreciated bya patient suffering miserable symptoms. Regimens of steroidtherapy vary between centres. There is no evidence to supportany particular regimen. Two commonly used regimens are:< A starting dose of 40 mg prednisolone per day, reducing by

5 mg/d at weekly intervals, or (for moderate disease).< 20 mg/d for 4 weeks then reduce by 5 mg/day at weekly

intervals.A standard weaning strategy helps identify patients who

relapse rapidly or do not respond and need adjunctive therapywith thiopurines or as an inpatient.

Steroid resistance or unresponsiveness should lead to escala-tion of treatment, or consideration of surgery. Medical therapiesinclude an immunosuppressive appropriate to the acuteness andtype of disease (typically thiopurine in moderate ulcerativecolitis or Crohn’s disease, anti-TNF therapy in Crohn’s diseaseand ciclosporin (or infliximab if ciclosporin is contraindicated) inacute severe ulcerative colitis). Escalation of therapy should beconsidered in the following situations:< any patient who has a severe relapse or frequently relapsing

disease< those who require two or more corticosteroid courses within

a 12 month period< those whose disease relapses as the dose of steroid is reduced

below 15 mg< relapse within 6 weeks of stopping corticosteroids

Adverse effects of steroidsThree broad groups can be identified, although 50% of patientsreport no adverse event.< Effects due to supra-physiological doses include cosmetic

(acne, moon face, oedema), sleep and mood disturbance,dyspepsia or glucose intolerance. The uncontrolled observa-tional data from the large TREAT registry suggests a twofoldRR of infection associated with steroid usage versus nosteroid usage and a twofold RR of mortality with prednis-olone. Steroids are also associated with increased risk ofinfections following surgery (OR 1.68 (1.24 to 2.28)).136 137

< Effects associated with prolonged use (usually >12 weeks,but sometimes less) include posterior subcapsular cataracts,

osteoporosis, osteonecrosis of the femoral head, myopathyand susceptibility to infection. Steroids have been associatedwith impaired growth velocity in some conditions. However,when strategies are taken to avoid steroids in Crohn’s disease,the main influence on growth velocity is disease activity.138

< Effects during withdrawal include acute adrenal insufficiency(from sudden cessation), corticosteroid withdrawal syndromeasyndrome of myalgia, malaise and arthralgia (similar torecrudesence of Crohn’s disease), or raised intracranialpressure.

Monitoring for side effectsOther guidelines recommend monitoring for eye, bone and otherside effects particularly in patients on steroids for more than3 months139 (see also section 7.6: Osteoporosis).

4.4.4 ThiopurinesAzathioprine (AZA) or mercaptopurine (MP) are widely used inulcerative colitis and Crohn’s disease as adjunctive therapy andas corticosteroid-sparing therapies although they are unlicensedtherapies for IBD. Their slow onset of action precludes usage assole therapy for active disease. Purine antimetabolites inhibitribonucleotide synthesis, but the mechanism of immunomodu-lation is by inducing T cell apoptosis by modulating cell (Rac1)signalling.140 AZA is non-enzymatically metabolised to MP,which involves loss of a nitro-imidazole side chain; this isthought to explain some of the side effects seen with AZA andwhich may be less of a problem with MP.141 142 MP is subse-quently metabolised to 6-thioguanine nucleotides (6-TGN).6-TGN has been used for treatment of IBD, but caution isappropriate because of potential hepatotoxicity.

Efficacy in ulcerative colitisAZA is more effective than mesalazine at induction of clinicaland endoscopic remission in steroid dependent ulcerativecolitis143 and should be first-choice therapy in this situationproviding other causes of persistent symptoms such as cyto-megalovirus or cancer have been excluded. Thiopurines areeffective maintenance therapy for patients with ulcerative colitiswho have failed or who cannot tolerate mesalazine and forpatients who require repeated courses of steroids, although thedata quality has been cited as poor in a recent Cochranereview144 and the evidence for using thiopurines in ulcerativecolitis is weaker than in Crohn’s disease: probably the best studyto date is Ardizzone et al143 which found steroid-free, clinicaland endoscopic remission in 53% patients on AZA comparedwith 21% given 5-ASA (OR on ITT 4.78, 95% CI 1.57 to 14.5).

Efficacy in Crohn’s diseaseThiopurines are effective for both induction and maintenance ofremission in Crohn’s disease. A Cochrane review of the efficacyof AZA and MP for inducing remission in active Crohn’s diseasedemonstrated a benefit for thiopurine therapy compared toplacebo with an OR of 2.43 (95% CI 1.62 to 3.64). This equatesto a number needed to treat (NNT) of about five and a numberneeded to harm (NNH) of 14.145 Their efficacy at maintainingremission is confirmed in another Cochrane review. The OR formaintenance of remission with AZA was 2.32 (95% CI 1.55 to3.49) with a NNTof six. The OR for maintenance of remissionwith MP was 3.32 (95% CI 1.40 to 7.87) with a NNT of four.Higher doses of AZA improved response. Withdrawals due toadverse events were more common in patients treated with AZA(OR 3.74; 95% CI 1.48 to 9.45, NNH¼20) than with placebo.146

For those who relapse once immunosuppressants are stopped,current evidence suggests that AZA/MP can be safely restarted

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and continued. The efficacy of thiopurines for post-operativeprophylaxis of Crohn’s disease is discussed in section 6.6.4.

DosingTailoring or optimisation of thiopurine therapy can occur priorto or during treatment. The appropriate maintenance dose ofAZA is 2e2.5 mg/kg/day and of MP is 0.75e1.5 mg/kg/day inboth ulcerative colitis and Crohn’s disease. The ‘maximum’ dosewill differ between individuals and effectively means that levelat which leucopenia develops. There is some evidence thatmesalazine has synergistic effects on thiopurine therapy but themechanism of this effect is unclear.147e149

Is measurement of thiopurine methyl-transferase necessary?AZA induced myelosuppression linked to thiopurine methyl-transferase (TPMT) deficiency and elevation of thioguaninenucleotide cytotoxic metabolites has been documented in manypatient groups including those with IBD.150 TPMT activity inhuman tissues is under the control of a common genetic poly-morphism. About 90% of the population have normal or highenzyme activity and are homozygous for the wild-type allele,10% inherit intermediate levels of enzyme activity with onewild-type and one variant allele, and one in 300 subjects have nofunctional TPMT activity.

Patients with leukaemia who are TPMT deficient are atincreased risk of myelotoxicity. This does not necessarily applyin IBD; in one study the majority (77%) of 41 patients with IBDwith AZA-induced bone marrow suppression did not carrya TPMT mutation. Evidence that TPMT activity predictsother side effects or outcome is limited.151 Patients with highlevels of TPMT may convert the majority of 6-MP into 6-MMPwith inadequate production of 6-TGNs to provide therapeuticefficacy.

The precise role of measuring TPMT levels in starting AZA/MP therapy is still controversial. At the start of AZA/MPtherapy, measuring TPMT has a role in identifying the one in300 patients at risk of severe immunosuppression when treatedwith standard doses. Most patients who develop leucopenia willhave a normal TPMT. During the initial months of AZA therapya knowledge of low TPMTactivity warns of possible early bonemarrow toxicity (probability of myelotoxicity in high TPMTgroup is 3.5% compared 14.3% in the TPMT intermediategroup.152 In patients established on AZA, there is no goodevidence to suggest that TPMT is predictive of clinical responseor drug toxicity, suggesting a role for TPMT in the prediction ofearly events rather than long-term control.153

Monitoring thiopurine therapyManufacturers recommend weekly full blood counts (FBCs) forthe first 8 weeks of therapy followed by blood tests at least every3 months. There is no evidence that this is effective. One fairlycommon practice is to perform a full blood count every2e4 weeks for 2 months and then every 4e8 weeks. The ratio-nale for this approach is that, of patients who develop thio-purine-associated myelotoxicity, approximately half will developit within 2 months and nearly two thirds within 4 months.154

The mean corpuscular volume is expected to rise on thiopurinesand can be used as a surrogate marker for rising 6-TGNconcentrations.155

Adverse effects of thiopurines145 146

Adverse events occur in up to 20%. The commonest are allergicreactions (fever, arthralgia, rash) that characteristically occurafter 2e3 weeks and cease rapidly when the drug is withdrawn.Profound leucopenia can develop suddenly and unpredictably, in

between blood tests, although it is rare (around 3% in a reviewof 66 studies).156 Bone marrow toxicity has been reported tooccur up to 11 years after starting AZA157 and blood monitoringshould continue throughout thiopurine therapy. Hepatotoxicityand pancreatitis are uncommon (<5%). Patients should beadvised to report promptly if a sore throat or any other evidenceof infection occurs.Although a significant proportion of patients experience

adverse effects with thiopurines (28% of 622 patients experi-enced side-effects in a recent Cochrane review) when the drug istolerated for 3 weeks, long-term benefit can be expected. Thio-purines can reasonably be continued during pregnancy if ulcer-ative colitis or Crohn’s disease has been refractory. In a study of155 men and women with IBD who were parents of 347 preg-nancies while taking MP there was no difference in miscarriage,congenital abnormality or infection rate in the thiopurine groupcompared to a control group. Thiopurine doses should bereduced in renal impairment. The effect and toxicity of AZA/MPis increased by concurrent administration of allopurinol, and wesuggest co-prescription be avoided.

Risk of malignancyOrgan transplant recipients who are prescribed thiopurines aspart of their immunosuppression are recognised to have anincreased risk of developing lymphoproliferative disorders.158 InIBD, large population-based studies have shown no increasedrisk.159 160 However, the data from studies examining patientsprescribed thiopurines has been conflicting. One meta-analysissuggested no increased risk of malignancy,161 whereas a secondsuggested a fourfold increased risk of lymphoma in patientswith IBD treated with AZA/MP compared with backgroundpopulation.162 More recently, a large prospective study followedalmost 20 000 consecutive patients over a 3-year period for theincidence of lymphoproliferative disorders. Those patientsreceiving maintenance thiopurines had a fivefold increased riskcompared to those who had previously or never received thedrug.163 In absolute terms, the risk remains very small (<1% riskafter 10 years of thiopurine use) and the benefits of AZAoutweigh any risks.164 The risk of lymphoma when a thiopurineis combined with Anti-TNF therapy is discussed later (seesection 4.4.7).There is an increased risk of non-melanoma skin cancer in

patients treated with thiopurines. Patients should be advised toavoid excessive sun exposure and use a high-strength sunblock.165

Risk of postoperative complications in patients on thiopurinesAvailable evidence generally does not suggest an increased rateof postoperative complications associated with immunosup-pressive use166 although there is one study which reportedan association with postoperative intra-abdominal septiccomplications.167

Duration of maintenance therapy with thiopurinesRecent evidence favours indefinite use of AZA/MP once remis-sion has been established. Fraser et al carried out a retrospectivestudy of 622 patients (272 Crohn’s disease, 346 ulcerative colitis)at a single centre treated over 30 years with AZA,168 and founda 60e75% relapse rate 3 years after stopping immunosuppres-sants with no effect of duration of AZA dosage. Lémann andcolleagues in GETAID carried out a randomised controlled studyof AZA withdrawal in patients with Crohn’s disease in long-term remission on AZA.169 Median durations of AZA therapyand of clinical remission were 68.4 months and 63.6 months

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respectively. They found an 8% relapse rate in those randomisedto continue AZA therapy compared with 21% relapse rate inthose randomised to stop AZA, with high CRP (>20 mg/l) andHb<12 being associated with increased RR. Subsequent follow-up of the cohort who stopped AZA has confirmed a high relapserate, with 14%, 53% and 63% relapsing at 1, 3 and 5 yearsrespectively.170 Kim et al looked at 120 patients who weretreated with MP for at least 6 months, achieved remissionwithin 1 year of therapy, and who were in prolonged clinicalremission without steroids (> 6 mo without steroids).171 For 84patients maintained on MP, cumulative relapse rates at 1, 2, 3,and 5 years were 29%, 45%, 55%, and 61%. For 36 patients whostopped MP, relapse rates at the same intervals were 36%, 71%,85% and 85%. Sex, disease distribution, disease duration, time toremission on MP and concomitant 5ASA use did not affectrelapse rates. Cassinotti et al found for ulcerative colitis thatdisease extent, lack of sustained remission during AZA, andduration of therapy may stratify the risk of relapse on AZAwithdrawal.172

4.4.5 MethotrexatePolyglutamated metabolites of methotrexate (MTX) inhibitdihydrofolate reductase, but this cytotoxic effect does notexplain its anti-inflammatory effect. Inhibition of cytokine andeicosanoid synthesis probably plays a role. At present MTX ispositioned as a second-line immunosuppressive agent in patientsresistant or intolerant of AZA or MP, although it is currentlyunclear whether thiopurines are any more efficacious than MTXfor induction or maintenance of remission in IBD.

Efficacy in Crohn’s diseaseMTX is effective for the induction173 and maintenance174

of remission in Crohn’s disease and may induce mucosalhealing.175 176 Evidence from a single large RCTof adult patientsdemonstrates that 25 mg/week of intramuscular MTX is moreeffective than placebo at inducing steroid-free remission at16 weeks (39% vs 19%; p¼0.025; NNT¼5).177 In a subsequentstudy patients who responded to induction therapy were rand-omised to 15 mg/week of intramuscular MTX. 65% of patientsin the treated group compared with 39% in the placebo groupwere in remission at 40 weeks (NNT¼4).178

Efficacy in ulcerative colitisNo comparable trials have addressed the role of MTX in theinduction or maintenance of remission in ulcerative colitis. Asingle RCT of low dose (12.5 mg once weekly) oral MTX wasnot shown to be efficacious at inducing or maintaining remis-sion179 and is the only study considered in the Cochranereview.180 The low dose and oral administration may account forthe disappointing response. Several retrospective series, usinglarger weekly doses, have published more promising data withresponse or remission rates up to 78% in patients with ulcerativecolitis resistant or intolerant of AZA or MP.181e184

Mode of deliveryParenteral administration (either subcutaneous or intramuscular)may be more effective that oral therapy and is recommended,although oral dosing may be more convenient. Studies in rheu-matoid arthritis indicate the bioavailability of intramuscularMTX is greater than oral administration and equivalent tosubcutaneous dosing.185 Consistent with this, a large RCT inrheumatoid arthritis demonstrated subcutaneous MTX is signif-icantly more effective than oral administration.186 To date thereis no comparable studies in IBD; however, small uncontrolled

series indicate that parenteral might be superior to oral admin-istration in maintaining remission187 188 and subcutaneous maybe as effective as intramuscular dosing.189

Monitoring therapyMeasurement of full blood count and liver function tests areadvisable before and within 4 weeks of starting therapy, thenmonthly. The same caveats as for monitoring thiopurine therapyapply. Patients should remain under specialist follow-up.

Adverse effects of methotrexate190 191

Side effects are reported by 27e49% of patients leading to drugdiscontinuation in 10e25% of MTX treated patients. Earlytoxicity from MTX is primarily gastrointestinal (nausea).Co-prescription of folic acid 5 mg (once a week, taken 3 daysafter MTX) limits GI side effects of nausea, vomiting, diarrhoeaand stomatitis. Long-term concerns are hepatotoxicity, pneu-monitis and opportunistic infections. A study of liver biopsies inpatients with IBD taking MTX showed mostly only mildhistological abnormalities, despite cumulative doses of up to5410 mg. Hepatotoxicity may be minimised by avoidingadministration in patients with significant alcohol consump-tion, type II diabetes, obesity and concurrent liver diseaseswhich may cause steatohepatitis. Surveillance liver biopsy is notwarranted, but if the alanine aminotransferase (ALT) doublesthen it is sensible to withhold MTX until it returns to normalbefore a rechallenge. The prevalence of pneumonitis has beenestimated to be two to three cases per 100 patient-years ofexposure, but large series have not reported any cases. MTX isteratogenic and should not be used in women or men consid-ering conception. It may persist in tissues for long periods;therefore conception should be avoided for 3e6 months afterwithdrawal of therapy. Breast-feeding is not recommended.192

Duration of therapyEvidence regarding duration of treatment with MTX is lackingand no recommendation can be given. A meta-analysis ofobservational studies reports remission rates of 75%, 53% and43% after 1, 2 and 3 years of treatment respectively.193 Prolongeduse may be considered if needed. Potential risks and benefitsshould be discussed on an individual basis.

4.4.6 Calcineurin inhibitorsCiclosporin (oral or intravenous, unlicensed therapy for ulcerativecolitis)Ciclosporin (CsA) is an inhibitor of calcineurin, which preventsclonal expansion of T cell subsets. It has a rapid onset of actionand is effective in the management of severe ulcerative colitis.

Efficacy in ulcerative colitisIntravenous CsA is rapidly effective as a salvage therapy forpatients with refractory ulcerative colitis, who would otherwiseface colectomy, but its use is controversial because of toxicityand long-term failure rate. The drug should rarely be continuedfor more than 3e6 months and its main role is a bridge tothiopurine therapy (see section 4.4.4). However, a Cochranereview has concluded that numbers in controlled trials are sofew (only 50)194 195 that there was limited evidence for CsAbeing more effective than standard treatment alone for severeulcerative colitis.196 At the time of writing there are two largeongoing controlled trials comparing CsA with infliximab in thetreatment of acute severe colitis.

Efficacy in Crohn’s disease197

CsA has no therapeutic value in Crohn’s disease.

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Monitoring therapyMeasurement of blood pressure, full blood count, renal functionand CsA concentration (aim for 100e200 ng/ml) are advisable at0, 1 and 2 weeks, then monthly. Blood cholesterol and magne-sium should be checked before starting therapy (see below).

Adverse effects of CsAMinor side effects occur in 31e51%, including tremor, para-esthesiae, malaise, headache, abnormal liver function, gingivalhyperplasia and hirsutism. Major complications are reported in0e17%, including renal impairment, infections and neurotox-icity. The risk of seizures is increased in patients with a lowcholesterol (<3.0 mmol/l) or magnesium (<0.50 mmol/l). Oraltherapy is an alternative in these circumstances. Prophylaxisagainst Pneumocystis carinii pneumonia is an individual decisiondependent on nutritional state, concomitant immunosuppres-sive therapy and duration of therapy, but other opportunisticinfections (eg, Aspergillus sp.) may be as common.

Toxicity can be reduced by using lower doses (2 mg/kg/dayintravenously),198 by oral microemulsion CsA,199 or by mono-therapy without corticosteroids.194

Thiopurines after ciclosporin for induction of remission of severeulcerative colitisCsA may be used as rescue therapy for steroid refractory acutesevere ulcerative colitis (see section 5.3), but is best discontinuedwithin 6 months because of nephrotoxicity. Consequently,immunosuppressives such as AZA or MP are often introducedwhile the patient is still on CsA and steroids are being tapered.The justification of thiopurines in this setting (even in patientswho may be 5-ASA naïve) is the high colectomy rate (36e69%) inthe 12 months following introduction of CsA.200 The evidencethat thiopurines reduce the risk of colectomy after an inductionperiod with CsA is largely retrospective.201e203 Marion followed29 patients for a median of 92 weeks and reported a 22% colec-tomy rate in those taking MP compared to 72% of those nottaking MP. Similar results have been reported from Chicago, with20% colectomy rate in those patients taking MP after CsAcompared with 45% colectomy rate in those not taking MP.204

The Leuven group report experience with 142 patients, of who118 (83%) had an initial response to CsA and avoided colectomyduring initial hospitalisation.200 Sixty-four (54%) subsequentlycame to colectomy; the rate in those already on AZA compared tothat in patients starting AZA concurrently with CsAwas 59% vs.31% (p<0.05). Life table analysis showed that 33% of patientscame to colectomy at 1 year, with a probability rising to 88% at7 years if CsA was used in patients already on AZA: Theconclusion from this is that CsA has little role for patients whohave failed AZA of an appropriate dose and duration.

TacrolimusTacrolimus is another calcineurin inhibitor often preferred in thetransplant setting to CsA. Data from one placebo controlled trialand several series show that tacrolimus is effective in thetreatment of steroid refractory thiopurine naïve ulcerativecolitis.205 (Correction in Gut 2006;55:1684, regarding a dosageerror in the abstract.)206e209

A dose is of 0.025 mg/kg tacrolimus twice a day shouldachieve trough levels of 10e15 ng/ml. Remission and colectomy-free survival are similar to oral and intravenous CsA. A directcomparison between tacrolimus and CsA has not been made.

4.4.7 Anti-TNF therapieshttp://www.bsg.org.uk/forum (accessed Oct 2010)

There are presently two biological agents licensed for thetreatment of IBD in the UK; both are monoclonal antibodies

against tumour necrosis factor a (anti-TNF). Infliximab (IFX) isa chimeric anti-TNF antibody, consisting of 75% human IgG and25% murine component that actively binds membrane-boundand soluble TNFa. IFX is given by intravenous infusion only.Adalimumab (ADA) is a humanised anti-TNF antibody, given bysub-cutaneous injection only. At the present time both agentsare licensed for the treatment of inflammatory Crohn’s diseasethat has failed to respond to standard immunosuppression (ie,corticosteroids and thiopurine or methotrexate therapy). IFX isalso licensed for ulcerative colitis and fistulating Crohn’s disease.

Efficacy in Crohn’s diseaseNumerous large RCTs have documented the efficacy of IFX andADA for both inflammatory and fistulating Crohn’s disease.

Efficacy for inflammatory Crohn’s disease210e212

A multi-centre, double-blind study in 108 patients withmoderate-to-severe Crohn’s disease refractory to 5-ASA, cortico-steroids and/or immunosuppressives, demonstrated an 81%response rate at 4 weeks after 5 mg/kg IFX compared with 17%given placebo. The duration of response varied, but 48% who hadreceived 5 mg/kg still had a response at week 12. The ACCENT-1study was the definitive re-treatment trial. Maintenance ofremission in 335 responders to a single infusion of IFX 5 mg/kgfor active Crohn’s disease (out of an initial 573) was examined.Patients were treated with placebo, 5 mg/kg or 10 mg/kg every8 weeks until week 46. At week 30, remission rates were 21% inthe placebo group compared to 39% in the 5 mg/kg group(p¼0.003) and 45% in the10 mg/kg group (p¼0.0002).ADA has demonstrated efficacy in moderate to severely active

luminal Crohn’s disease in both anti-TNF naïve patients and inthose who failed IFX therapy. In CLASSIC-I, 30% of patientstreated with ADA (160/80 mg or 80/40 mg) entered clinicalremission versus 12% given placebo (p¼0.004).213 The remissionrate at week 4 reached 35.5% in those patients loaded with 160/80 mg ADA. The GAIN study demonstrated efficacy in patientswho had previously failed IFX therapy (4 week remission ratesof 21.4% vs. 7.2% placebo treated, p¼0.0006), albeit with lowerremission rates than in CLASSIC-I.214 There was no statisticaldifference in GAIN between those failing IFX due to intoleranceor as primary non-responders. The efficacy of maintenancetherapy has been conclusively demonstrated by the CLASSIC-IIand CHARM studies.215 216

Efficacy for fistulating Crohn’s disease217 218

Present et al treated 94 patients with draining abdominal or peri-anal fistulas of at least 3 months’ duration with IFX. 68% in the5 mg/kg group and 56% in the 10 mg/kg group experienceda 50% reduction in the number of draining fistulas at two ormore consecutive visits (4 weeks apart) versus 26% given placebo(p¼0.002 and p¼0.02, respectively). However, the duration ofthis effect was in most cases limited to only 3 or 4 months. Ina large re-treatment trial for fistulating Crohn’s disease(ACCENT-II), 306 patients with actively draining abdominal orperianal fistulae were treated with three induction infusions ofIFX 5 mg/kg at week 0, 2 and 6. 195/306 (69%) responded andthese were randomised to 5 mg/kg maintenance infusions orplacebo every 8 weeks. Patients who lost response were switchedfrom placebo to active treatment at 5 mg/kg, or the re-treatmentdose increased from 5 to 10 mg/kg. At the end of the 12 monthtrial, 46% of the patients on active re-treatment had a fistularesponse versus 23% on placebo (p¼0.001). Complete response(all fistulae closed) was observed in 36% of patients on activetreatment, compared to 19% on placebo (p¼0.009). Evidence forfistula healing with ADA was provided in the CHARM study

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where complete fistula healing was noted in 33% compared with13% given placebo at week 56 (p¼0.016) and thereafter main-tained to 2 years in an open-label extension.215

In the UK, NICE has issued new guidance for clinicians on theuse of IFX and ADA for the treatment of Crohn’s disease http://guidance.nice.org.uk/TA187 (accessed Oct 2010) (summarisedbelow) that offers a pragmatic approach to maintenancetherapy. The IBD committee endorses this approach but recog-nises that practice in this area differs from some other nations.Several aspects, especially the optimal selection of patients andtiming of stopping anti-TNF therapy lack a strong evidence baseat this time and it is likely that practice will evolve in the nearfuture.

Efficacy in ulcerative colitisAt present, only IFX has been shown to be effective in ulcerativecolitis. A recent Cochrane review of seven RCTs showed thatIFX (three intravenous infusions at 0, 2 and 6 weeks) was moreeffective than placebo in inducing clinical remission (OR 3.22,95% CI 2.18 to 4.76); inducing endoscopic remission (OR 1.88,95% CI 1.54 to 2.28) and clinical response (OR 1.99, 95% CI 1.65to 2.41) at 8 weeks.219 ACT1 was a 364 patient study inmoderately active ulcerative colitis refractory to oral steroidsand/or thiopurines, given placebo, IFX 5 mg/kg or 10 mg/kg, at0, 2 and 6 weeks, then every 8 weeks for a year.220 The primaryendpoint at week 8 (clinical response defined as >30% anda three-point decrease in the Mayo activity index, with virtual

cessation of rectal bleeding) was reached by 37.2% (placebo),69.4% (5 mg/kg) and 61.5% (10 mg/kg), p>0.001). Thesecondary endpoints of remission (14.9%, 38.8% and 32.0%respectively) and mucosal healing (33.9%, 62.0%, and 59.0%)were also achieved. Duration of effect was maintained throughweek 30 with rates of remission: 15.7%, 33.9% and 36.9%,p>0.001). In ACT2,220 an almost identical trial of a further 364patients, where outpatients with moderately active ulcerativecolitis refractory to 5-ASA could be included, the rates ofresponse and remission at week 8 were 29.3%/5.7%, 64.5%/33.9% and 69.2%/27.5% in placebo, 5 mg/kg and 10 mg/kgrespectively (p>0.001). Significantly higher rates of mucosalhealing were also demonstrated. Despite these positive findings,only 20.9% in the ACT1 study were in corticosteroid-freeremission at 1 year follow-up. Colectomy rates at 54 weeks haverecently been published and show an absolute risk reduction of7% in the IFX treated group.221

There are no published RCTs examining the efficacy of ADAin ulcerative colitis. However, case series suggest that ADA mayhave a role in treating mildemoderate ulcerative colitis patientswho are intolerant, or have lost response to IFX.222e225

Efficacy for corticosteroid-refractory ulcerative colitisIn a RCT involving 43 patients, Probert et al showed that IFXwas not superior to placebo in inducing remission at week 6(39% vs 30% remission rates in IFX and placebo groups respec-tively; p¼0.76).226 In this study, 77% of patients had received

NICE guidance for the use of Adalimumab and Infliximab in the treatment of Crohn’s Disease

1.1 Infliximab and adalimumab, within their licensed indications, are recommended as treatment options for adults with severe activeCrohn’s disease (see 1.6) whose disease has not responded to conventional therapy (including immunosuppressive and/or corticosteroidtreatments), or who are intolerant of or have contraindications to conventional therapy. Infliximab or adalimumab should be given asa planned course of treatment until treatment failure (including the need for surgery), or until 12 months after the start of treatment,whichever is shorter. People should then have their disease reassessed (see 1.4) to determine whether ongoing treatment is still clinicallyappropriate.1.2 Treatment as described in 1.1 should normally be started with the less expensive drug (taking into account drug administration costs,required dose and product price per dose). This may need to be varied for individual patients because of differences in the method ofadministration and treatment schedules.1.3 Infliximab, within its licensed indication, is recommended as a treatment option for people with active fistulating Crohn’s disease whosedisease has not responded to conventional therapy (including antibiotics, drainage and immunosuppressive treatments), or who areintolerant of or have contraindications to conventional therapy. Infliximab should be given as a planned course of treatment until treatmentfailure (including the need for surgery) or until 12 months after the start of treatment, whichever is shorter. People should then have theirdisease reassessed (see 1.4) to determine whether ongoing treatment is still clinically appropriate.1.4 Treatment with infliximab or adalimumab (see 1.1 and 1.3) should only be continued if there is clear evidence of ongoing active diseaseas determined by clinical symptoms, biological markers and investigation, including endoscopy if necessary. Specialists should discuss therisks and benefits of continued treatment with patients and consider a trial withdrawal from treatment for all patients who are in stableclinical remission. People who continue treatment with infliximab or adalimumab should have their disease reassessed at least every12 months to determine whether ongoing treatment is still clinically appropriate. People whose disease relapses after treatment is stoppedshould have the option to start treatment again.1.5 Infliximab, within its licensed indication, is recommended for the treatment of people aged 6e17 years with severe active Crohn’sdisease whose disease has not responded to conventional therapy (including corticosteroids, immunosuppressives and primary nutritiontherapy), or who are intolerant of or have contraindications to conventional therapy. The need to continue treatment should be reviewed atleast every 12 months.1.6 For the purposes of this guidance, severe active Crohn’s disease is defined as very poor general health and one or more symptoms suchas weight loss, fever, severe abdominal pain and usually frequent (3e4 or more) diarrhoeal stools daily. People with severe active Crohn’sdisease may or may not develop new fistulae or have extra-intestinal manifestations of the disease. This clinical definition normally, but notexclusively, corresponds to a Crohn’s Disease Activity Index (CDAI) score of 300 or more, or a HarveyeBradshaw score of 8 to 9 or above.1.7 When using the CDAI and HarveyeBradshaw index, healthcare professionals should take into account any physical, sensory or learningdisabilities, or communication difficulties that could affect the scores and make any adjustments they consider appropriate.1.8 Treatment with infliximab or adalimumab should only be started and reviewed by clinicians with experience of TNF inhibitors and ofmanaging Crohn’s disease.

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corticosteroids for more than 14 days. In the ACT1/2 studies,a third of the patients were considered to be refractory tocorticosteroids at the time of recruitment. Contrary to theearlier study, the response (not remission) rates were signifi-cantly higher than placebo at week 8 (77% vs. 35%, p<0.001).220

NICE has not approved the use of IFX in subacute setting(defined as outpatient basis) (http://guidance.nice.org.uk/TA140(accessed Oct 2010)) based on the lack of cost effectiveness.

Efficacy for acute severe ulcerative colitisJarnerot et al in a RCT involving 45 patients comparing a singleinfusion of IFX (5 mg/kg) and placebo showed significantlylower colectomy rates within 90 days of therapy (primary end-point; p¼0.017, OR 4.9).227 This study had a parallel designwhere either patients with a fulminant colitis index228 $8.0 onday 3 after institution of high dose intravenous corticosteroids;or a Seo index on day 5, 6, or 7 satisfying the criteria of a severeor moderately severe attack of ulcerative colitis unresponsive tostandard therapy were included. In sub-group analysis, thepatients in the latter group derived the most benefit from IFXtherapy (p¼0.009).

Current NICE guidelines reccommend the use of ciclosporinas first-line therapy in steroid refractory acute severe ulcerativecolitis (and IFX use only if ciclosporin is contraindicated) basedon health economic analyses and the paucity of data to supportthe use of IFX over ciclosporin (http://www.nice.org.uk/nice-media/pdf/TA163Guidance.pdf (last accessed Oct 2010)). TheCONSTRUCT UK trial will assess the comparative efficacy ofIFX versus ciclosporin in the acute severe ulcerative colitissetting, (http://www.crncc.nihr.ac.uk/ (last accessed Oct 2010)).The GETAID group are also due to report on a separate study(CYSIF) in this context.

Adverse effects of anti-TNF therapyDue to the nature of their effects on TNF, all anti-TNF therapiesshare a similar profile of adverse events, including increased riskof infections from intracellular pathogens, most notably, TB,other opportunistic infections, autoimmunity, infusion reac-tions, and other more rare side-effects. This should be balancedwith the potential curative option of surgery in ulcerativecolitis.

InfectionsWhen considering this side effect of anti-TNF therapy, it isimportant to put it in context of corticosteroids and immuno-suppressives, which also increase the risk of infectious compli-cations. Toruner et al demonstrated that the respective use ofcorticosteroids, immunosuppressives or infliximab conferreda threefold increased risk of developing an opportunistic infec-tion that increased to 15-fold when two or more therapies areused in combination.229

In the Scottish severe ulcerative colitis cohort of 38 patients,infliximab treatment as rescue therapy was associated with twoserious adverse events: death secondary to pseudomonas pneu-monia, and fungal septicaemia post-operatively.230 The recentMayo Clinic experience shows that chronic ulcerative colitispatients treated with IFX before ileo-anal pouch anastamosishave substantially increased the odds of postoperative pouch-related and infectious complications (odds ratio 2.7, CI 1.1 to6.7). In this cohort, there was no mortality associated withIFX therapy.231 Further cohort studies have reported increasedpost-operative complications attributed to IFX,232 and increasedpost-operative complications attributed to corticosteroid use butnot IFX.233 A subsequent meta-analysis has reported anincreased risk of all post-operative complications with pre-

operative IFX use.234 Sub-group analysis was underpowered, butthere was a trend towards increased infections.IFX therapy is associated with an increased risk of tuberculosis

(TB).235 Pre-treatment screening for exposure to TB is importantvia a history, chest x-ray and tuberculin skin test if applicable. TheBritishThoracic Societyhasproduced guidance for assessing risk ofTB and managing disease in patients who are about to beginanti-TNF therapy (http://www.brit-thoracic.org.uk/Portals/0/Clinical%20Information/Tuberculosis/Guidelines/antitnf.pdf).236

Where treatment for latent TB is needed 12 weeks therapy isrecommendedprior to initiation of anti-TNF therapy. Prophylactictreatment reduces the risk of TB by 70%.237 Diagnosis of latent TBin patients with IBD on immunosuppressives is difficult astuberculin skin testing has a high false negative rate. Tcell inter-feron-gamma release assays are amore specific andprobably amoresensitive test for diagnosis of M tuberculosis infection than thetuberculin skin testing in immunocompetent persons. Results arenot affected by prior BCG vaccination. Data also suggest thatresults are unaffected by immunosuppression but are affected bycurrent anti-TNF therapy.238 There is insufficient evidence atpresent to recommend the use of interferon-gamma release assays,but NICE is examining their utility (http://guidance.nice.org.uk/CG/Wave0/103 (last accessed Oct 2010)).Re-activation of chronic hepatitis B has been reported

in patients treated with IFX.239 There are no data to suggestanti-TNF therapy has any effect on the course of chronichepatitis C. Pre-treatment screening for exposure to hepatitis Bis important; vaccination should be considered in the non-immune high-risk patient. (see sections 6.0 and 7.8).

Antibody formationAntibodies to infliximab (ATI) can trigger both acute infusionreactions and delayed serum-sickness-like reactions. Minor acutereactions usually respond to slowing the infusion rate or treat-ment with antihistamines, paracetamol and sometimes corti-costeroids. Anti-histamines and steroids can be used aspremedication to minimise anaphylactic reactions, which can besevere, especially after a prolonged drug holiday. Episodictherapy and consequent ‘drug holiday ’ is associated withincreased formation of ATIs, and should be avoided. In theACCENT 1 study, the cumulative incidence of ATI was 30%through 72 weeks, significantly higher than the 10% and 7% inthe group of patients treated with systematic treatment with 5or 10 mg/kg infliximab infusion every 8 weeks. ATI formation isassociated with increased incidence of infusion reactions and lossof response.240

Although ADA is a fully humanised antibody, it is also asso-ciated with the formation of antibodies to adalimumab (ATA)which have been shown to reduce efficacy in rheumatoidarthritis241 and Crohn’s disease.242

There is emerging evidence linking low serum trough levels ofIFX to lack of sustained response.243 244 Further research isrequired, but it appears serum IFX levels are influenced by ATIsand otherdprobably pharmacokineticdfactors. At this stage, itis not known what the target trough level should be.245 In theUK this issue is at present academic because there is no availablecommercial resource for measuring either trough levels or anti-body levels. We think such a resource would be valuable.

MalignancyIn a pooled analysis using results of placebo-controlled trials ofIFX and ADA in patients with rheumatoid arthritis, the OR formalignancy (including basal and squamous cell cancers) was 3.3(95% CI, 1.2 to 9.1).246 Of note, while 11 of the reported 35

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malignancies in anti-TNF patients were lymphomas or leukae-mias, 14 were solid organ cancers. The findings of this contro-versial meta-analysis were not observed in the TREAT registry137

and the Leuven dataset.247 In the combined analysis of 484patients with ulcerative colitis who received IFX in the ACT trialsthere were four malignancies presenting in the trial periodcompared with one basal cell carcinoma in the 244 who receivedplacebo. In an analysis of 38 patients from six English centresmaintained on 8-weekly IFX infusions (median follow-up15 months), there was one case of invasive breast carcinomadeveloping during treatment phase.248 The Mayo Clinic practiceand Edinburgh series confirmed the relatively rare occurrence ofmalignancy.249 250 However, some observations in these twolatter studies serve to highlight possible groups of patients athigher risk of developing certain malignancies. In the Mayo Clinicseries of 500 Crohn’s disease patients, two lung cancers, boththought ‘possibly related’ to IFX were reported in elderly smokers;and three lung cancers in 207 patients in the Edinburgh cohort.The Edinburgh group recently reported a case of non-small-celllung cancer which resolved when anti-TNF therapy was discon-tinued.251 A recent 24-week trial of IFX in COPD was notable forthe high malignancy rate in 157 IFX treated patients (ninemalignancies including four lung cancers plus two additional lungcancers after study completion vs. 1/77 in placebo group).252

There is a recognised risk of non-Hodgkin’s lymphoma (NHL).Of recent particular concern is the recent reported cluster of therare hepato-splenic T cell lymphoma in Crohn’s disease.253 Thisis now reported in both IFX and ADA therapy (17 cases in total)and also in ulcerative colitis (three cases).254 All except one wereconcomitantly treated with thiopurines; and the outcomes havebeen almost uniformly fatal. It is uncertain whether this isa combined cumulative effect of anti-TNF and thiopurinetherapy. However, it is important to note that initial fearsthat there would be an epidemic of HSTL in anti-TNF treatedpatients have not been realised, with stable incidence rates. Arecent meta-analysis examined the rate of NHL in adultCrohn’s disease in those who have received anti-TNF therapyand compared that to the rate in a population-based registry,and to the rate in those exposed to immunosuppressantsalone.255 Anti-TNF therapy was associated with an increasedrisk of NHL when compared to the general population, but therisk remained small (6.1 per 10 000 patient-years). Anti-TNFtherapy also led to an increased rate of NHL compared tothose treated with immunosuppressants alone, although thisdid not reach significance. One difficulty with interpretingthese findings is that the majority of NHL cases patients hadbeen exposed to immunosuppressants at some point. Thio-purines alone are associated with in increased risk oflymphoma162 163 and it is difficult to establish the relativecontribution of each drug.

DemyelinationReports of optic neuritis, seizure, and new onset or exacerbationof central nervous system demyelinating disorders, includingmultiple sclerosis, have been reported with the use of all anti-TNFs. It is also noteworthy that in multiple sclerosis,a controlled trial of anti-TNF therapy (lenercept) resulted ina significantly increased risk of exacerbation of disease.256 Thismay be relevant in high incident populations.

Congestive cardiac failureAnti-TNF agents are contraindicated for patients with classIIIeIV congestive heart failure due to evidence of increased risksof death from several clinical trials.

Unresolved issues concerning the use of anti-TNF therapyhttp://www.bsg.org.uk/forum (accessed Oct 2010)< In newly diagnosed patients with Crohn’s disease, which

patients should be offered early anti-TNF therapy? The top-down approach257 does not address this specific area and infact, results in over-treatment in a considerable subset ofpatients with anti-TNF therapy (30%). This also has healtheconomic implications.

< It is unclear as to whether patients should be treated withsolely anti-TNF monotherapy or with concomitant immuno-suppression. The balance of argument pivots on the need tooptimise anti-TNF therapy and the increased risk of compli-cations associated with the latter. The recent SONIC studyevaluated as primary end-point the efficacy at 26 weeks of IFXmonotherapy, AZAmonotherapy and the two drugs combinedin 508 patients with active Crohn’s disease who had notpreviously undergone immunosuppressive or biologicaltherapy. On combination therapy, 56.8% were in steroid-freeremission at week 26, compared with 44.4% of patients on IFXmontherapy (p¼0.02), and 30.0% on AZA alone (p<0.001). Asimilar trend was reported at week 50. The study did notaddress longer-term efficacy, safety, cost-issues, or withdrawalstrategies, nor identify key prognostic factors for response toAZA alone, all critical issues in clinical practice.258

< In patients stably maintained in clinical remission (on anti-TNF monotherapy or combination therapy), it is unclear howlong therapy should continue or whether patients shouldwean off anti-TNF therapy or immunosuppressant therapy.In a small study of AZA withdrawal after 6 months ofcombination therapy (n¼80), continuation of immunosup-pressants offered no clear benefit over scheduled IFXmonotherapy.259 However, a similar study (n¼48) reportedIFX failure rates of 15% and 59% at 1 and 2 years respectively.Relapse was more likely in those with on-going inflamma-tion.260 NICE recommends re-assessing the requirement foranti-TNF at 12 months, but there is no evidence to supportany strategy. Emerging data in abstract form suggests thatIFX may be discontinued and successfully re-introduced ifpatients relapse.

< Could there be additional long term or unforeseen safetyrisks? Although a number of single-centred or tertiary anti-TNF experiences have been reported,247 249 250 261 a frame-work to track and register any therapy-related complicationsthat occur in clinical practice is necessary. This is particularlyrelevant in the face of the likely expansion in anti-TNF use,choice of anti-TNF agents and other newer biologics. Theexisting framework is not yet sufficiently robust to identifythe more rare adverse events. For example, in pregnancy,a review of the FDA database reported 61 anomalies in 41children exposed to anti-TNF agents in utero. Of thesechildren, 24/41 (59%) had one or more congenital anomaliesthat are part of the vertebral abnormalities, anal atresia,cardiac defect, tracheoesophageal, renal, and limb abnormal-ities (VACTERL) association. There were 34 specific types ofcongenital anomalies in total, and 19 (56%) of those werepart of the VACTERL spectrum.262 This study as beencriticised for the lack of denominator and the fact that therewas only one complete VACTERL anomaly, while otherdefects were mostly cardiac in origin. Further study is clearlywarranted and caution advisable. A national biologics registeris in progress. In general, the BSG committee favoursa cautious measured approach to anti-TNF and other newbiologics therapy in line with the primum non nocere principle.

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5.0 MANAGEMENT OF ULCERATIVE COLITIShttp://www.bsg.org.uk/forum (accessed Oct 2010)

Therapeutic decisions depend on disease activity and extent.Disease activity is best evaluated objectively using a clinicalactivity index (the Truelove and Witts263 or the Mayo Clinicdisease activity index.264 Patients with severe disease requirehospital admission, while those with mild/moderate disease cangenerally be managed as out patients.

Disease extent can broadly be divided into distal and moreextensive disease. However disease extent can vary (increase ordecrease) with time in about 30% of patients. Topical manage-ment is appropriate for some patients with active disease. This isusually the case for those with proctitis and often the case if thedisease extends into the sigmoid. For those with more extensivedisease, oral or parenteral therapy is the mainstay of treatment,although patients may get additional benefit from topical therapy.

5.1 Active left-sided or extensive ulcerative colitis7 82e86 103 265

Ulcerative colitis phenotype is determined by the maximalextent of inflammation observed at colonoscopy.23 ‘Left-sided’ulcerative colitis (E2) is defined as disease extending proximal tothe recto-sigmoid junction up to the splenic flexure; ‘extensive’ulcerative colitis (E3) as extending proximal to the splenicflexure (table 3). Disease activity should be confirmed bysigmoidoscopy and infection excluded, although treatment neednot wait for microbiological analysis.

Recommendations for the treatment of active (left-sided orextensive) ulcerative colitis:< Oral mesalazine 2.4e4.8 g daily or balsalazide 6.75 g (deliv-

ering 2.4 g mesalazine) daily are effective first-line therapy formildemoderately active disease (EL 1a, RG). Topical mesala-zine combined with oral mesalazine >2 g/day is moreeffective than oral therapy alone for both left-sided (EL 1b,RG B) and extensive colitis (EL1b, RG A).

< Once daily dosing with mesalazine is at least as effective astwice or three times daily regimes.

< Prednisolone 20e40 mg daily is appropriate for those patientswith moderately active disease, in whom mesalazine inappropriate dose and route has been unsuccessful (EL1b, RG C).

< Prednisolone should be reduced gradually according toseverity and patient response, generally over 8 weeks. Morerapid reduction is associated with early relapse.

< (For acute severe ulcerative colitis, see section 5.3).

5.2 Active proctitis7 83 89 129 266e269

Patient preference has a greater influence on management thanfor extensive colitis, in view of the option between topical orsystemic therapy. Choice of topical formulation should bedetermined by the proximal extent of the inflammation(suppositories for disease to the recto-sigmoid junction, foam orliquid enemas for more proximal disease) along with patientpreference, such as ease of insertion or retention of enemas.

Proximal faecal loading is common in patients with distalcolitis and may relate to a defect in colonic motility.269 It isa common cause of a patient not responding to apparentlyadequate therapy and is easily seen on a plain abdominal radio-graph. Stool bulking agents are often not helpful: non-stimulantosmotic laxatives such as a polyethylene glycol (PEG)-basedpreparation are often helpful.

Recommendations for the treatment of active proctitis< In mildemoderate disease, topical mesalazine 1e2 g daily (in

appropriate form for extent of disease) may be effective alone.

Combination with oral mesalazine 2e4 g daily, or balsalazide6.75 g daily, may be useful in resistant cases. (EL1b, RG B).

< Topical corticosteroids are less effective than topical mesala-zine, and should be reserved as second-line therapy forpatients who are unresponsive to topical mesalazine (EL 1b,RG B).

< Patients who have failed to improve on a combination of oralmesalazine with either topical mesalazine or topical cortico-steroids should be treated with oral prednisolone 40 mg daily.Topical agents may be used as adjunctive therapy in thissituation (EL1b, RG A).

< In the management of proximal faecal loading associatedwith distal colitis, non-stimulant osmotic laxatives such asa PEG-based preparation are often helpful (EL 3, RG C).

< Refractory proctitis should prompt exclusion of alternativepathology, consideration of drug compliance, change offormulation, associated irritable bowel, and further escalationof therapy.7

5.3 Acute severe ulcerative colitis194 195 198 227 270e272

Acute severe ulcerative colitis is a medical emergency. It is bestdefined by the Truelove and Witts’ criteria263 (ulcerative colitispatients with $6 bloody stools/day and signs of systemictoxicity (HR>90, T>37.8, Hb#10.5 or ESR>30)). Patientsshould be admitted for intensive intravenous therapy.Intensive inpatient treatment with intravenous corticoste-

roids and early surgical intervention has reduced the UKmortality from acute severe ulcerative colitis to 2.9%.9 Seventyper cent of the deaths have significant co-morbidity. However,the colectomy rate in acute severe ulcerative colitis (w30%) hasnot changed in 40 years.272 Acute ulcerative colitis is sometimesdifficult to distinguish from infective colitis; treatment shouldnot be delayed until stool microbiology results are available. Itmay be appropriate to commence both corticosteroids andantibiotics.< The IBD service should have arrangements in place to admit

known patients with IBD direct to the specialist gastroen-terology ward or area.

< Patients admitted with known or suspected IBD shoulddiscussed with and normally be transferred to the care ofa consultant gastroenterologist/colorectal surgeon within24 h of admission.

< Where these facilities are not available (especially where thereis no dedicated colorectal surgical service on site), patientsshould be transferred to appropriate centre for on-going jointmedical-surgical management.Important steps in the initial management include:

< Patients should be weighed and their nutritional needsassessed (IBD Standard A10). If the patient is malnourishednutritional support by the enteral route is associated withfewer complications than the parenteral route in acutecoilitis.273

< Full blood count, urea and electrolytes, liver function tests,serum albumin, glucose and CRP, and haematinics (iron, B12,folate).Stool culture and C difficile toxin assay. Microbiological testing

for C difficile. Toxin in addition to standard organisms inincreasingly important. C difficile infection has a higher preva-lence in patients with IBD through unknownmechanisms, maynot be confined to the colon, and is associated with increasedmortality. A minimum of four stool samples are required todetect 90% of cases.34 35 Cytomegalovirus (CMV) should beconsidered in severe or refractory colitis as reactivation iscommon in patients with IBD on immunosuppression and the

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presentation can mimic ulcerative colitis or Crohn’s disease.CMV colitis is associated with a poor outcome and high colec-tomy rate.274e276 A combination of colonic histology and PCRfor viral DNA confirms the diagnosis rapidly. Immunosuppres-sants should be discontinued in favour of intravenous Gancy-clovir for 2 weeks or the more expensive but equally effectiveoral agent Valgancyclovir. Further management is described inthe ECCO consensus statement on prevention, diagnosis andmanagement of opportunistic infections in IBD.277

< Intravenous fluid and electrolyte replacement to correct andprevent dehydration or electrolyte imbalance, with bloodtransfusion to maintain a haemoglobin >10 g/dl.

< Intravenous antibiotics only if infection is considered, orimmediately prior to surgery. Withdrawal of anticholinergic,antidiarrhoeal agents, opioid drugs, which risk precipitatingcolonic dilatation.

< Subcutaneous heparin to reduce the risk of thromboembolism.278

< Intravenous corticosteroidse Either hydrocortisone 100 mg four times a day or

methylprednisolone 60 mg/day (EL1b, RGB).eHigher doses of steroids offer no greater benefit, but lower

doses are less effective.< If there is evidence of toxic megacolon (diameter >5.5 cm, or

caecum >9 cm), the urgency with which surgery is under-taken after recognition of colonic dilatation depends on thecondition of the patient: the greater the dilatation and thegreater the degree of systemic toxicity, the sooner surgeryshould be undertaken, but signs may be masked by steroidtherapy. In selected patients with mild dilatation, expectantmanagement may be undertaken.

< Any clinical, laboratory or radiological deteriorationmandates immediate colectomy.

< Flexible sigmoidoscopy and biopsy should be available within72 h (ideally within 24 h) and a histological diagnosis within5 days to confirm diagnosis and exclude CMV. (IBD StandardA9)Daily monitoring:

< Physical examination daily to evaluate abdominal tendernessand rebound tenderness. Joint medical and surgical manage-ment is appropriate (EL5, RG D).

< Recording of vital signs four times daily and more often ifdeterioration noted.

< Stool chart (to record number and character of bowelmovements, including the presence or absence of blood andliquid versus solid stool).

< Measurement of FBC, CRP, serum electrolytes, serumalbumin, liver function tests and glucose every 24 h.

< Consider need for daily AXR especially if there are signs ofcolonic distension and/or there is significant deterioration inclinical condition or blood parameters.Further decision making:

< A stool frequency of >8/day or CRP >45 mg/l at 3 daysappears to predict the need for surgery in 85% of cases.270

Surgical review and input from specialist colorectal nurse orstoma therapist is appropriate at this stage.

< Intravenous steroids are generally given for up to 5 days.There is no benefit beyond 7e10 days.272

< Consideration of colectomy or rescue therapy with eitherintravenous ciclosporin (CsA) 2 mg/kg/day OR infliximab(IFX) if there is no improvement by day 3 or there issubsequent deterioration (EL1b, RG B). NICE recommendsCsA as first-line (and IFX use only if CsA is contraindicated)based on health economic analyses and the paucity of data tosupport the use of IFX over CsA (http://www.nice.org.uk/

nicemedia/pdf/TA163Guidance.pdf (accessed Oct 2010)). Forpatients already on immunosuppressive therapy such asAZA/MP at the time of presentation, surgery should beconsidered as the first option (EL4, grade D).

< Rescue with intravenous CsA:e 2 mg/kg/day is as effective as 4 mg/kg/day with decreased

toxicitye Magnesium, cholesterol and creatinine should be measured

within 48 h of starting CsAeBeware contraindications (Mg2+<0.5 mM or cholesterol

<3.0 mM) and be vigilant for toxicitye Following induction of remission, oral CsA for 3e6 months

is appropriate. (EL 1b, RG B).e Intravenous CsA alone may be as effective as methylpred-

nisolone, but potential side effects mean that it is rarely anappropriate single first line therapy (EL1b, RG C).< Rescue with IFX:

e dose induction of 5 mg/kg (0, 2 and 6 weeks). The side-effects of IFX, including therapy associated risk of mortality,should be discussed fully prior to its initiation (EL2, grade C).

e IFX maintenance therapy in ulcerative colitis is notrecommended because of the low corticosteroid-free remissionrates after 1 year, and the limited data on subsequent need forcolectomy (EL1b, grade C).

e IFX should be given as a ‘bridge’ to longer termimmunosuppressive therapy such as AZA/MP.< If no response to rescue therapy is seen within 4e7 days,

colectomy is recommended (EL5, RG D). Specifically, we donot recommend CsA after IFX or vice versa (EL5, RG B).Other factors to consider:

< The long-term follow-up of patients following an attack ofacute severe ulcerative colitis reveals 50% of those who do notenter complete remission with steroids will require colectomywithin 1 year.279

< Patients who avoid surgery should be considered formaintenance therapy with a thiopurine. (see section 4.2.4).

< On discharge, oral steroids should be tapered over8 weeks. Supplementation with calcium and vitamin D isrecommended.280

5.4 Maintenance of remission7 82 84 90 93 103 105 157 168 265

Long-term maintenance therapy is generally recommended forall patients, especially those with left-sided or extensive disease,and those with proctitis who relapse more than once a year.Discontinuation of medication may be reasonable for those withdistal disease who have been in remission for 2 years and areaverse to such medication. The role of anti-TNF is discussedearlier and NICE does not approve use.

Recommendations for the maintenance of remission in ulcerativecolitis:< Patients with ulcerative colitis should normally receive

maintenance therapy with aminosalicylates, azathioprine,or mercaptopurine to reduce the risk of relapse.

< Oral mesalazine 1.2e2.4 g daily or balsalazide 4.5 g dailyshould be considered as first-line therapy (EL1b, RG A).

< Topical mesalazine 1 g daily may be used in patients withdistal disease with/without oral mesalazine, but patients areless likely to be compliant. (EL1b, RG B).

< For patients on maintenance aminosalicylates, annualmeasurement of creatinine is sensible, although there is noevidence that monitoring is necessary or effective atpreventing renal impairment. Aminosalicylates should bestopped if renal function deteriorates.

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< Long-term treatment with steroids is unacceptable. If steroidscannot be withdrawn, surgery should be considered.

< AZA 2e2.5 mg/kg/day, or MP 0.75e1.5 mg/kg/day are thefirst line agents of choice for steroid-dependent disease.144

AZA is significantly more effective than mesalazine atinducing clinical and endoscopic remission in the treatmentof steroid dependent ulcerative colitis.143 (EL1b, RG A) Thesedrugs should be considered in the following situations:e any patient who has a severe relapse or frequently relapsing

diseasee those who require two or more corticosteroid courses

within a 12 month periode those whose disease relapses as the dose of steroid is

reduced below 15 mge relapse within 6 weeks of stopping corticosteroidse following ciclosporin (CsA) for induction of remission of

severe ulcerative colitis (see section 4.4.6)< All patients should have measurement of thiopurine methyl-

transferase (TPMT) levels before starting thiopurines, mainlyto avoid administration to a patient with no functionalTPMT in whom thiopurine administration may be fatal (EL4,RG B)

< For patients in remission, cessation may be considered after4 years of full remission (EL2, RG C), but a small treatmentbenefit persists even after 6 years (EL1b, RG B). Benefits andrisks of continuing thiopurines should be discussed withindividual patients.

< Methotrexate may be considered in the treatment of patientswho do not respond to or are intolerant of thiopurines (EL4,RGC). Optimal duration of therapy is not established.

< If first-line immunosuppressive therapy fails, several factors(patient’s wishes, fecundity, patient age and extent of disease)need to be taken into account and a suitable therapeuticstrategy to achieve steroid free remission discussed. In manycases this may necessitate surgery.

IBD service standards< There must be local protocols for prescribing and monitoring

of thiopurines. Local practice should be audited (IBDStandard A6).

5.5 Surgery for ulcerative colitishttp://www.bsg.org.uk/forum (accessed Oct 2010)

Up to 30% of patients will ultimately require colectomy forulcerative colitis.26 27 281 The decision to operate is best taken bythe gastroenterologist and colorectal surgeon in conjunctionwith the patient.

5.5.1 indications< Disease not responding to intensive medical therapy< Presence of dysplasia or carcinoma (see section 7.2)< poorly controlled disease< recurrent acute on chronic episodes of ulcerative colitis< retained rectal stump following previous colectomy.

5.5.2 OperationsThere is debate over the efficacy and safety of on-going medicaltherapy versus surgery in patients with acute severe colitis whofail initial high dose corticosteroids. Second-line medical therapymay reduce the need for immediate colectomy and yet manypatients will relapse and require subsequent colectomy.279

Furthermore, second-line medical therapy carries with ita definable mortality risk200 and in comparison, in experienced

surgical hands, subtotal colectomy and ileostomy remains a safealternative.282

Sub-total colectomyThe operation of choice in patients with acute severe colitisfailing to respond to intensive medical treatment is a subtotalcolectomy, end ileostomy and preservation of a long rectalstump. The stump can be over-sewn and remain in the perito-neal cavity, sutured to the abdominal wall fascia beneath theskin or be delivered as a mucous fistula. The choice of what to dodepends upon the severity of disease in the rectum at the time ofsurgery.283 It is not recommended that patients undergo the ileo-anal pouch procedure (IAPP) at this stage; they are often unwell,with low albumin and on high-dose steroids. A clinical colorectalnurse specialist in stoma therapy should perform preoperativecounselling and marking of stoma sites.

Ileo-anal pouch procedurePatients requiring elective surgery for ulcerative colitis should becounselled regarding all surgical options. Surgery usuallyinvolves panproctocolectomy with permanent end ileostomy orIAPP. The choice between these two options is based uponpatient preference and clinical criteria (ie, dysplasia/malignancy,sphincter injury or dysfunction). In appropriately selected casesit is difficult to find a difference in terms of quality of lifebetween the two.284 There remain a number of controversiessurrounding the IAPP with regard to technique:1. one- versus two-stage procedures2. hand-sewn or stapled pouch3. pouch configuration (W, S, J)4. hand-sewn or stapled ileo-anal anastomosesThe data to support one or any of these variations remains

limited and it is difficult to be precise regarding recom-mendations.285e290 Many of the choices rely on surgical judge-ment and surgical expertise. IAPP is a technically demandingprocedure and carries with it a significant morbidity rate andthis morbidity relates to subsequent functional and quality oflife outcomes.291e296

In addition, there is evidence that the success of IAPP in termsof this functional and quality of life outcome is related to someextent to the experience of the surgeon operating297 and thevolume of the hospital practice.298 Furthermore, there isemerging evidence that units with greater experience of pouchsurgery are better equipped to manage the complications andconsequently preserve or improve outcome.299 It has thereforebeen suggested that surgical units undertaking IAPP should beperforming at least ten cases per year as a minimum.7

5.5.3 complications and functional outcomeSub-total colectomyAs a result of the severity of illness complications post surgeryare significant. Failure of healing and sepsis being commonespecially with patients on high does corticosteroids. There isevidence that delay in surgery as a result of prolonged first orsecond line medical therapy may increase morbidity.300e302 Thisis further evidence for co-operative management of thesepatients by senior gastroenterologists and surgeons.

Ileo-anal pouch procedureWhile the functional outcomes following pouch procedures arefavourable it remains a technically demanding procedure.Complication rates can be significant and pouchitis remains apersistent and difficult problem (section 5.6).303 Clinical outcomesafter pouch surgery are variable in publishes series.295 304 The

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latest data to emerge from the UK pouch registry suggest thatthe incidence of failure, defined as excision or indefinite diver-sion, was 7.7% following primary salvage. The medianfrequency of defaecation/24 h was five including one at night.Nocturnal seepage occurred in 8% at 1 year, rising to 15.4% at20 years (p¼0.037). Urgency was experienced by 5.1% ofpatients at 1 year rising to 9.1% at 15 years (p¼0.022).305

Fecundity of young women may be reduced by 40�50%following IAPP, probably as a result of pelvic surgery andsubsequent pelvic adhesions.306e308 Appropriate informedconsent, and an exploration of alternative medical or surgicaloptions should be undertaken in women of childbearing poten-tial before IAPP.

Recommendations for surgery in ulcerative colitis< surgical units undertaking IAPP should be performing at least

10 cases per year as a minimum (EL5, RG D).

IBD Service Standards: (A7)< expert pathological assessment before surgery is important< IBD surgery should be undertaken by colorectal surgeons in

a unit where the operations are performed regularly< pouch failure and salvage should be managed in a high-

volume specialist unit

5.6 Pouchitishttp://www.bsg.org.uk/forum (accessed Oct 2010)

Up to 50% of patients who undergo ileal pouch surgery forulcerative colitis suffer from pouchitis.291 Symptoms includeincreased looseness and frequency of stool with or withoutbleeding. Urgency, tenesmus and pelvic discomfort in addition tofever and systemic upset may also occur.309

Diagnosis of pouchitis requires an appropriate clinicalpresentation in addition to endoscopic and histological confir-mation of inflammation.310 Conditions that mimic pouchitis(cuffitis, pelvic sepsis, prepouch ileitis, irritable pouch) should beconsidered.311e313

Treatment of pouchitisA number of trials exist to support the use of antibiotics and probi-otics in the treatment and prevention of pouchitis.63 64 113 119 314e317

Other agents have been used in resistant pouchitis includebudesonide,318 319 ciclosporin,320 short-chain fatty acids,321 andinfliximab.322 A Cochrane review has recently summarised thedata.323

Recommendations for pouchitis< The diagnosis of pouchitis should normally be made on

clinical and endoscopic and histological criteria (EL1a, RG A).< Metronidazole 400 mg three times a day (EL1a, RG A) or

ciprofloxacin 250 mg bd (EL1b, RG B) for 2 weeks is the first-line therapy of choice for pouchitis.

< Long-term, low-dose metronidazole or ciprofloxacin arepotentially effective for chronic pouchitis (RG B).

< VSL#3 probiotic therapy may be used to treat and preventpouchitis (EL2b, RG B). Its efficacy is lost soon after stoppingthe treatment.

6.0 MANAGEMENT OF CROHN’S DISEASEThe general principles are to consider the site (ileal, ileocolic,colonic, other), pattern (inflammatory, stricturing, fistulating)and activity of the disease before treatment decisions are made inconjunction with the patient. Assessing the severity of Crohn’sdisease can be more difficult in comparison to ulcerative colitis.

An alternative explanation for symptoms other than activedisease should be considered (such as infection, abscess forma-tion, bacterial overgrowth, bile salt malabsorption, dysmotility,gall stones) and disease activity confirmed before initiating newtherapies. Routine blood tests including FBC, CRP and albuminprovide an index of disease activity in some, but not all patients.The need for further imaging by endoscopy, barium radiology,CT scanning, MRI, EUA or capsule endoscopy should beconsidered in each individual patient. Smoking cessation shouldbe strongly advised before discussion of any drug therapy (EL2b,RG C). NSAIDs are not recommended for pain relief in IBD. IfNSAID administration is unavoidable, careful follow-up issuggested, as disease aggravation requires drug discontinuation(EL2b, RG B). Primary nutritional therapy should not be over-looked. Elemental or polymeric diets are less effective thancorticosteroids, but may be used to induce remission in selectedpatients with active Crohn’s disease who have a contraindica-tion to corticosteroid therapy, or where patients/physicanswould prefer to avoid corticosteroids. (EL2b, RG C). Efficacy isless in isolated colonic disease than small bowel diseaseand adherence a problem, especially in adults. Exclusive enteralnutrition (EEN) is appropriate as disease-modifying therapy forgrowth failure, and in adults may be used for those inwhom corticosteroids are contraindicated or declined, or inpatients who prefer EEN (EL2a, RG B). Before initiatingbiological therapy, steroids, or immunosuppression, infectionneeds to be rigorously excluded, and the potential role of surgeryre-evaluated.Complex cases should be discussed at a MDT meeting.

Careful discussion with each patient as to the likely benefits/risks of new therapies must be part of the decision-makingprocess; these discussions should be documented in writing.

6.1 Active ileal, ileocolonic, or colonic Crohn’sdisease2 3 32 75 84 145 146 173 177 178 210e218

http://www.bsg.org.uk/forum (accessed Oct 2010).In some, such as those with incidental disease detected at

bowel cancer screening, therapy may not be required. In others,surgical review may be necessary at an early stage, often beforeinitiating steroids, biological therapies or immunosuppressives.Early surgery may be preferable to medical therapy with manypatients, and physicians. The risk of surgical complications isincreased by delay to surgery, prolonged steroid usage, andmalnutrition.324 325 Evidence for the use of antibiotics in short-term therapy of colonic disease is available for metronidazoleand ciprofloxacin. In practice, this form of therapy is limited forpatients with refractory disease, or contra-indications to othertherapies for which a stronger evidence basis exists.Infliximab and adalimumab are efficacious in inducing and

maintaining remission in patients with active luminal Crohn’sdisease and fistulating disease affecting the perineum (seebelow). The drugs are relatively contra-indicated in the presenceof fibrostenotic disease, where surgical intervention is likely tobe more appropriate. However, they may be preferable inextensive colitis or small bowel disease. Analysis of risks andbenefits of anti-TNF drugs needs be undertaken, balancedagainst other therapeutic alternatives and discussed withpatients. In practice these discussions are best held in a multi-disciplinary setting. The lack of evidence for anti-TNF therapy ina number of key areas needs to be addressed where possible bycontrolled trials: specifically, duration of therapy, long-termsafety, and role of combination therapy. Current evidence andclinical experience now clearly favours scheduled maintenancetherapy over episodic use of these agents.

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Recommendations for active ileal, ileocolonic, or colonic Crohn’sdisease< Initial treatment of active ileal or ileo-colonic Crohn’s disease

should be tailored to the severity of disease and must take theviews of the patient into account.

< For patients with moderately active disease requiringtreatment, oral corticosteroids such as prednisolone20�40 mg, or budesonide 9 mg daily is appropriate (EL1a).Prednisolone should be reduced gradually according toseverity and patient response, generally over 8 weeks. Morerapid reduction is associated with early relapse. If steroids aregiven, concomitant bone protection is recommended (seesection 7). Budesonide 9 mg daily is appropriate for patientswith isolated ileo-caecal disease with moderate diseaseactivity. Although marginally less effective than predniso-lone, its side-effect profile is substantially better (EL1b).

< Failure to wean corticosteroids is common, and shouldbe regarded as a treatment failure necessitating furtherintervention.

< In patients with severe active Crohn’s disease, or diseaserefractory to corticosteroids, anti-TNF therapy may be usedin induction of remission, and in subsequent maintenance(see sections 4.4.7 and 6.2 for a detailed discussion ofevidence, treatment strategies, and uncertainties that needto be addressed).

< AZA, MP and MTX are efficacious in inducing remission, buteach limited by time to response, side-effects, and uncer-tainties regarding drug withdrawal (see section 6.2)(EL1b, RGA).145 146 326

< Refractory active Crohn’s disease remains an area for clinicaltrials of new therapies, supported by the National Institute ofHealth Research Portfolio, (http://www.crncc.nihr.ac.uk/(accessed Oct 2010)).

IBD Service Standards< Access to a dietician and nutritional support should be

available to all patients with IBD (Standard A5).< Nutritional assessment should be performed on diagnosis and

each hospital admission. Adolescents should have regularmonitoring with height and weight centile charts and6-monthly assessment of pubertal status (Standard A10).

6.2 Maintenance of remissionhttp://www.bsg.org.uk/forum (accessed Oct 2010).

The majority of patients treated with steroids will not be inremission after 1 year133 and will therefore require maintenancetherapy. Smoking cessation is probably the most importantfactor in maintaining remission and reducing the risk of relapsein Crohn’s disease.

Recommendations for maintenance of remission of Crohn’s disease< AZA or MP should be considered as first line treatment for

patients in the following situations (see section 4.4.4 fordetails):e any patient who has a severe relapse or frequently relapsingdisease

e those who require two or more corticosteroid courseswithin a 12 month period

e those whose disease relapses as the dose of steroid isreduced below 15 mg

e a relapse within 6 weeks of stopping corticosteroids< MTX is effective for patients whose active disease has

responded to IM methotrexate (EL1b, RG A). It is appropriate

for those intolerant of, or who have failed to respond tothiopurines (EL2, RG B) once potential toxicity and otheroptions, including surgery, have been discussed with thepatient (see section 4.4.5 for details).

< Anti-TNF therapy is effective in maintaining remission inCrohn’s disease (EL1a, RG A), although long-term data arelacking. It is best used as part of treatment strategy includingimmunomodulation once other options, including surgery,have been discussed with the patient. Treatment with ADAor IFX should only be started and reviewed by clinicians withexperience of managing Crohn’s disease with anti-TNFtherapy (http://guidance.nice.org.uk/TA187 (accessed Oct2010)). Concurrent infection/sepsis should be excluded (seesection 4.4.7) and treatment delayed until appropriateinvestigations (eg, cultures/imaging/examination underanaesthesia) and treatment (eg, antibiotics/surgical drainage)concluded.

Practical guidance in the use of anti-TNF therapies in induction andmaintenance strategies< For IFX, the dosing regimen is as follows:

eA dose of 5 mg/kg IFX is used with loading doses at 0, 2and 6 weeks:

e If no evidence of initial response after two doses (primarynon-responders), reconsider overall medical and surgicalmanagement of patient. Switch to ADA or dose intensifica-tion to 10 mg/kg can be considered but with caution as datasupporting these strategies are not strong (EL4, grade C).

e If there is evidence of initial response, scheduled mainte-nance therapy will usually be appropriate. This is giveninitially at 8-weekly intervals (EL1b, RG B). Whereresponse is lost, a valid initial strategy is to decreaseinfusion interval (initially to 6 weeks; no more frequentthan 4-weekly) or to dose intensify by a single dose of10 mg/kg or to switch to ADA (EL4, RG C).

< IFX should be used for fistulating Crohn’s disease only afterensuring that all sepsis is actively draining; this requiresappropriate cross sectional imaging (eg, MRI pelvis) andclose collaboration with experienced colo-rectal surgeons(EL3, RG B).

< Pre-dosing with hydrocortisone is not usually required withthe recommended scheduled maintenance IFX therapy.

< Initial infusions of IFX should be given over 2 h with closemonitoring in a dedicated infusion facility, by trainedpersonnel. Subsequent doses can be given over 1 h327 (EL4,RG D).

< If re-treatment with IFX is required after a significant ‘drugholiday ’ (>12 months) following initial IFX therapy, highvigilance is required for acute and chronic infusion reactions.Consider switching to alternative agent (ie, ADA) (EL5, RGD).

< For ADA the induction regimen can be 80 mg/40 mg sc onsuccessive weeks, or 160 mg/80 mg215 (EL1b, grade B). The80 mg/40 mg loading regimen is associated with a highrequirement for subsequent does escalation.261 (EL4, grade C).The alternative of 160/80 mg may be more effective inpatients who have lost response/intolerant to IFX.214 (EL2,grade C)eMaintenance therapy is 40 mg every other weeke If response is lost, then escalate to 40 mg every weeke If response is regained, it may then be possible todecrease dosing back to 40 mg every other week (EL5,RG D)

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< For ADA therapy, the patient or relative/carer should betaught appropriate injection technique by an IBD nursepractitioner. Patients should be given clear advice aboutintercurrent illness (especially infection), when to delaytreatment and who to contact for further advice.

< A medical history of demyelinating illness or optic neuritis isa relative contraindication for anti-TNF therapy (EL2b, RGC). In patients with a family history of demyelination, anti-TNF therapy should be used with caution or avoided ifpossible. In this context, the risk of subsequent demyelin-ating episode is unclear. Expert neurological advice may besought.

< The initiation of anti-TNF therapy during pregnancy shouldonly be considered following full risk counselling with patient(and partner) particularly its unknown long-term effects.This should also be counterbalanced against risk of activedisease in pregnancy and be applicable in patients alreadyon maintenance anti-TNF therapy in Crohn’s disease (seesection 7).

< Anti-TNF therapy should only be used with caution in olderpatients (>65 years old) with significant smoking histories. Ifused in this situation, we suggest a CXR every 6e12 months(EL2b, RG C).

< We suggest particular caution in the use of anti-TNF therapyin patients with a medical history of malignancy.

< Anti-TNF therapy should be avoided in patients withcongestive cardiac failure (EL2, RG B). In elderly patients orthose with pre-existing ischaemic heart disease, the presenceof cardiac failure should be screened (EL1b, RG B).

< NICE recommends that maintenance with anti-TNF therapyshould continue until treatment failure (including the needfor surgery) or until 12 months after the start of treatment,whichever is shorter: The disease should then be reassessed.Maintenance therapy should only then be continued if thereis clear evidence of ongoing active disease as determined byclinical symptoms and investigation (http://guidance.nice.org.uk/TA187 (accessed Oct 2010)).

IBD service standards< There must be local protocols for prescribing and monitoring

of thiopurines. Local practice should be audited (IBDStandard A6).

< Treatment with anti-TNF therapy should only be initiated byclinicians with expertise in their use for IBD (IBD StandardB1).

< Multi-disciplinary team meeting (IBD Standard A3).< Where maintenance anti-TNF therapy is considered, it is

recommended that the patient’s case is discussed at multi-disciplinary IBD meeting where colorectal surgeons are alsopresent. Of note, it should be considered at this stage whetheror not surgery represents a more appropriate intervention fora particular patient.

< Counselling (IBD Standard C3)< The risks and benefits of treatment should be discussed with

the patients and documented in the medical case records. Inview of insufficient evidence with respect to several key issuessurrounding the long-term use of immunosuppressivetherapy and anti-TNF therapy, limitations in knowledgeneed to be discussed with each patient. One mechanism offormalising such a discussion is the provision of formalconsent. It is recommended that this conversation include thediscussion of:e EfficacyeAlternative treatment options, including surgery

eRisks of infection, infusion reactions, malignancy(including hepatosplenic T cell lymphoma), demyelinationand drug-induced lupus

eWritten information should be provided (IBD Standard D1)

6.3 Perianal Crohn’s disease4

http://www.bsg.org.uk/forum (accessed Oct 2010)The cumulative risk of developing a perianal fistula is

approximately 10% at 1 year, 15% at 5 years and 20% at10 years.328 Fistulae were noted in 12% of patients with ilealdisease, 15% with ileocolic disease, 41% with colonic and 92%with rectal involvement.329

Management principles329e335

The first priority in the management of patients presenting withperianal sepsis/fistula is to establish early and adequate surgicaldrainage. Clinicians should not be tempted to wait for theresults of imaging investigations but should involve the appro-priate surgical team to urgently examine the patient undergeneral anaesthesia and to drain collections of pus. The nextpriority is to assess the extent of the disease. This can, in part, beachieved at the time of the surgical examination. In addition,MRI or ultrasound will help establish disease activity in theperineum. Luminal investigation is important to establishdisease elsewhere, in particular in the rectum as this mayinfluence longterm outcomes. At this stage patients with simpleand low perianal fistulae in the absence of rectal involvementcan be treated with conventional surgical lay open. Patientswith more complex disease or with rectal involvement needprimary medical management and ‘adjuvant’ surgicalintervention.

Recommendations for perianal Crohn’s diseaseMedical treatment4 145 146 210 217 218 257 331 336e341

< Metronidazole 400 mg three times a day and/or ciprofloxacin500 mg bd are appropriate first-line treatments for simpleperianal fistulae (EL4, RG D) (see section 4.2).

< AZA 2e2.5 mg/kg/day or MP 0.75e1.5 mg/kg/day arepotentially effective for simple perianal fistulae or enter-ocutaneous fistulae where distal obstruction and abscess havebeen excluded (EL4, RG D).

< Anti-TNF therapy may be used in patients with severeperianal or enterocutaneous fistulae or who are refractory toother treatment, and should be used as part of a pathwaythat includes immunosuppression and surgery.

Surgical treatment. Surgery should be used in conjunction withbest medical therapy. Seton drainage can be a useful technique toprovide symptom control and can be used as a prelude tomedical treatment.342 343 Other surgical approaches such asadvancement flaps, and fistula plugs may be appropriate forpersistent or complex fistulae in combination with medicaltreatment.344

There is insufficient evidence to recommend other agents suchas tacrolimus ointment and local infliximab outside clinical trialsor specialist centres.

6.4 Non-perianal fistulating Crohn’s disease4

http://www.bsg.org.uk/forum (accessed Oct 2010)This includes fistulae communicating with other viscera

(urinary bladder, vagina), loops of intestine (enteroenteralfistulae), or the abdominal wall (enterocutaneous fistulae). Thereis a notable lack of controlled data in this field.

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Management of non-perianal fistulating Crohn’s diseaseThere are no RCTs on the effect of medical treatment for non-perianal fistulating Crohn’s disease, other than the subgroups ofthe ACCENT II trial. Less than 10% of the patients in theACCENT II trial receiving infliximab therapy had abdominalenterocutaneous fistulae. For the 25 (of 282) patients withrectovaginal fistulae in the ACCENT II trial, infliximab was onlymodestly effective (45% closure at week 14).

Recommendations for entero-gynaecological fistulae< Low anal-introital fistula may be almost asymptomatic and

not need surgical treatment (EL5, RG D).< If the patient has a symptomatic fistula, surgery is usually

necessary (including diverting ostomy) (EL5, RG D).< Rectovaginal fistulae failing conservative treatment should

have surgery with an advancement flap and/or divertingostomy if they are associated with unacceptable symptoms(EL5, RG D).

< Intestinal small bowel or sigmoid-gynaecological fistulae canusually be treated with resection of the diseased bowelsegment (EL5, RG D).

Recommendations for enterovesical fistulae< Surgery is the preferred approach for enterovesical fistulae

(EL5, RG D). Only in high-risk patients (after multipleoperations and\or severely shortened bowel), should medicaltherapy be the first option (EL5, RG D).

Recommendations for enterocutaneous fistulae< Post-surgical enterocutaneous fistulae should initially be

treated with nutritional support and anatomical definition(EL5, RG D). Surgery after an interval is appropriate oncenutrition is restored.

< Primary enterocutaneous fistulae can be treated medically butwill generally require surgical management (by resecting thediseased bowel segment) (EL5, RG D).

6.5 Other sitesThe same general principles apply, although there are no rand-omised controlled trials.

Oral Crohn’s diseaseThis is best managed in conjunction with a specialist in oralmedicine. Topical steroids, topical tacrolimus, intra-lesionalsteroid injections, exclusion diets, enteral nutrition, and inflix-imab may have a role in management but there are no rando-mised controlled trials.

Gastroduodenal diseaseDisease in this area is associated with a poorer prognosis.345

Most clinicians would add a proton pump inhibitor to theconventional induction/maintenance therapies. Case reportsdescribe a good outcome with anti-TNF therapy.346 Surgery isdifficult and may be complicated by fistulation.

Post-surgical anastomotic stricturesEndoscopic dilatation is an effective and safe treatment for shortstrictures and can delay requirement for further surgery.347

Injection of steroids into strictures may cause more harm.348

6.6 Surgery for Crohn’s diseasehttp://www.bsg.org.uk/forum (accessed Oct 2010)

6.6.1 General principlesDuring the lifetime of a patient with Crohn’s disease, surgery maybe required in up to 75% of patients after 10 years of disease,

dependent on disease location.349 In addition, despite clear changesin the effective medical management of Crohn’s disease, evidenceto date would suggest that there has been little change in thenatural history of the disease and hence the need forsurgery.349e351 Despite this the decision to operate remains diffi-cult. On the one hand complication rates and recurrence ratesafter surgery are relatively high.352 On the other hand, there isclear evidence that surgery provides good long-term disease controlin many patients353 354 and that delay in operating may result inmore advanced disease and hence more postoperative complica-tions.324 325 The debate has been further fuelled by concerns overthe effect of medical therapy on surgical complication rates. Itseems clear that the preoperative use of steroids certainly doesincrease the subsequent surgical risk but current evidence suggeststhat immunosuppressive or biological agents do not.301 355

Laparoscopic surgery appears safe and feasible in Crohn’sdisease and is emerging as the procedure of choice for ileocolicresections.356 The benefits seem to be related to an improvementin early postoperative recovery, a reduction in wound complica-tions and a cosmetic advantage. There is emerging evidence thatthere may be longer-term advantages in reducing subsequentadhesive complications and making subsequent resection in theevent of recurrence possible laparoscopically as well.357e360

The management of colonic Crohn’s disease is perhaps morecontroversial. Segmental resection of isolated disease carriesa higher recurrence rate but has all the functional benefits ofcolonic preservation. It would appear that the benefits are mostobvious in right-sided disease and in patients with only one ortwo segments of isolated disease. Patients with predominantlyleft-sided disease or more than two areas involved do better witha subtotal colectomy and ileo-rectal anastomosis if the rectum isspared, or a panproctocolectomy and permanent ileostomy if therectum is involved.361e363

6.6.2 Indications for surgeryThere are few randomised data to support decisions aboutsurgery in Crohn’s disease and multidisciplinary meetings todiscuss these issues are invaluable. Surgical intervention isgoverned by the extent of the disease, the response to medicaltreatment and the presence or absence of complications.Fibrostenotic and fistulating intestinal disease with or withoutassociated sepsis respond poorly to medical therapy; inthe presence of a limited ileocolic distribution surgery is a goodtherapeutic option. In more extensive disease, preservationof bowel length is critically important. Limiting the resectionto macroscopic disease and the use of strictureplasty haverevolutionised surgery in this scenario.364e367

Recommendations for surgery in Crohn’s disease (IBD ServiceStandards: A7)< Expert pathological assessment before surgery is important.

This may involve referral to a recognised expert in thedifferential diagnosis of IBD.

< IBD surgery should be undertaken by colorectal surgeons (ortheir supervised trainees), who are core members of the IBDteam in a unit where the operations are performed regularly.

6.6.3 Postoperative management: preventing postoperativerecurrencehttp://www.bsg.org.uk/forum (accessed Oct 2010)Most patients with ileo-caecal Crohn’s disease who undergo

surgical resection will develop recurrent disease in the neo-terminalileum: endoscopic recurrence rates are 73% and 85% at 1 and

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3 years, respectively.352 With no further medical therapy, clinicalrecurrence rates are about 20�30% at 1 year, with a 10% increaseper year in subsequent years.368 Observed recurrence rates arelower in patients who undergo resections from other sites.369

The most characterised risk factor for postoperative relapse issmoking. For patients who smoke, cessation significantlyreduces post-operative relapse.75 78

There has been some debate as to whether the technique ofsurgical anastomosis influences postoperative recurrence. Earlyreports suggested that a wide lumen stapled technique led tosignificant reduction in recurrence as well as an increased time torecurrence.370 371 A meta-analysis suggested that these differ-ences were at best minimal although the side-to-side anasto-mosis seemed to be associated with less complication anda lower leak rate than more traditional end-to-end techniques.372

Most recently a randomised multicentre trial has beencompleted to specifically address the issue of surgical anasto-motic technique and recurrence. They concluded that there wasno difference in recurrence rates between the two groups withthe endoscopic recurrence rate being 42.5% in the end-to-endanastomosis group, compared with 37.9% in the side-to-sideanastomosis group at a mean follow-up of 11.9 years.373

6.6.4 Medical therapy to prevent relapseAt present, the evidence in favour of any specific medicalintervention in the prevention of postoperative setting is weak,and open to criticism. While European guidelines suggest the useof mesalazine or thiopurines in this setting,4 a critical appraisalof the quality of evidence does not permit us to endorse thisview, and we point to the need for randomised clinical trials toidentify risk factors for recurrence, to define the efficacy ofcurrently available agents and the optimum timing of intro-ducing and withdrawing these agents in this setting. Manyclinicians will feel that it is necessary to rely on their clinicalexperience of treating active disease in deciding on therapy forthe postoperative setting (in the absence of appropriateevidence) and prescribe thiopurines, metronidazole or mesala-zine in perceived high-risk patients.374

MesalazineThe use of mesalazine therapy has been studied in postoperativeprophylaxis in nine randomised clinical trials. Meta-analysis hasbeen carried out but needs to be seen in the context of theheterogeneity of the designs of these trials; drug formulation,dosage, inclusion criteria, end-points, and duration of follow-updiffered substantially and one trial was open-label rather thanblinded. In the meta-analysis, the absolute risk differencebetween placebo, and mesalazine therapy is 10%, a finding ofquestionable clinical relevance.374

ThiopurinesThe two trials often quoted in support of thiopurine use in thiscontext are now well-recognised as being substantiallyflawed.374

In a trial with no pre-specified primary end-points, Hanaueret al375 used a fixed dose of 50 mg MP with no doseeweightcorrection. The investigators demonstrated a statisticallysignificant benefit over placebo at 2 years; however, by this stage56% patients had withdrawn from the study, a factor thatinevitably limits the interpretation of the data.

Ardizzone376 compared AZA to mesalazine in postoperativeprevention. There was no placebo group, and the two therapiesshowed no difference in the co-primary end-points of clinical andsurgical recurrence at 2 years. Only a speculative post hoc sub-

analysis showed a benefit for AZA in patients who had previouslyundergone a surgical resection. Problems in the design of thisstudy are many and include the fact that the study was openlabel, not blinded, the lack of endoscopic confirmation of clinicalend-points, and finally the fact that the trial evaluated onlyconservative surgery such as strictureplasty or mini-resectionallowing patients with residual active disease to be included.A meta-analysis of four of 15 potentially eligible studies

including the two mentioned above looked at a total of 198patients treated with AZA/MP and 235 control patients treatedwith mesalazine, placebo or metronidazole. It suggests that theeffect of thiopurines in preventing postoperative recurrence isreal but modest, averaging 8�13% at 1 year for clinical recur-rence and 15% for endoscopic recurrence.377

We do not feel that any currently available evidence favours useof antibiotics, probiotics, prebiotics, corticosteroids, methotrexateor biologicals in this context; there are ongoing trials assessing theefficacy of infliximab in preventing postoperative recurrence.The ECCO consensus algorithm for management has been

well received by many clinicians, with the objective of makingdecisions in high-risk patients on the basis of perceived riskfactors as well as endoscopic appearances at 6 months. However,we point out that the strength of evidence to support riskfactors other than smoking habit is weak, and the delay ininstituting treatment until 6 months is such that this strategyshould be interpreted as a treatment strategy for active disease,rather than primary prophylaxis.

6.6.5 Other considerationsParenteral vitamin B12 supplementsThere is some dispute about the length of resection required toproduce deficiency of vitamin B12. Patients with less than 20 cmof ileal resection do not develop deficiency, while 52% of thosewith longer resection have abnormal Schilling tests.378 Resectionof more than 60 cm almost invariably results in vitamin B12deficiency.379 A practical approach is to treat with parenteralvitamin B12 all patients with more than 20 cm resected andmeasure serum B12 yearly in those with less than 20 cm resected.

Bile salt malabsorptionBile salt malabsorption occurs when normal active uptake fromthe ileum via the apical sodium dependant bile acid transporteris disrupted by ileal inflammation or resection, and results inwatery diarrhoea. The degree of malabsorption depends on thelength of ileal involvement or resection.380 Diagnosis of bile saltmalabsorption can be made via SeHCAT scanning, althoughmeasurement of plasma lathosterol381 or serum 7-a-hydroxycholestenone382 appears to give similar sensitivity in a simplerand less expensive test. Treatment is either with cholestyramineor a newer sequestrant such as colesevalam, which is morepotent and better tolerated.

Recommendations for prevention of postoperative recurrence ofCrohn’s disease< Patients who smoke should be strongly advised to stop and

offered help to achieve this (EL2b, RG C).

7.0 ASSOCIATED ASPECTS OF INFLAMMATORY BOWELDISEASE4 5

7.1 Management of pain and fatiguehttp://www.bsg.org.uk/forum (accessed Oct 2010)Abdominal pain is a common but under-researched feature of

IBD. There are many potential mechanisms. These include acuteand sub-acute obstruction in Crohn’s disease due to disease or

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adhesions, serosal and mucosal inflammation, visceral hyper-sensitivity, secondary irritable bowel syndrome, proctalgia fugax,the likely impact of emotional factors on pain thresholds andvisceral distension where there is dilation. Gallstones, renalcalculi and chronic pancreatitis should be considered. In addition,arthritis, iritis and painful skin complications require analgesia inmany patients. Most analgesics are relatively ineffective and havethe potential to worsen underlying disease. Where possible,treatment is of the underlying cause (including corticosteroidsand if appropriate, treatment of associated irritable bowelsyndrome). Where non-specific pain relief is needed, an opioidthat has less effect on motility, such as tramadol, may help.

Patients with active and quiescent IBD often report symp-toms of fatigue. Studies have demonstrated that fatiguemeasurement scores in patients with IBD are comparable toscores reported in cancer patients.383 As yet no identifiable causehas been found for ongoing fatigue in the absence of activedisease; however, in patients complaining of this symptom it isimportant to exclude any clinical cause including anaemia andsub-therapeutic maintenance medication doses.

In patients in whom no identifiable cause can be found, thesymptom should not be ignored as it can have significantconsequences on the individuals’ quality of life, affecting work,school and social factors. More data is required on interventionstrategies in this area.

7.2 Surveillance for colonic carcinoma28 93 384e387

http://www.bsg.org.uk/forum (accessed Oct 2010)Evidence relating to the increased incidence of colorectal

carcinoma and the need for surveillance is reviewed in the ECCOconsensus document.5 Recommendations reflect those publishedin the British Society of Gastroenterology ColonoscopicSurveillance Guidelines.388 Extensive colitis is defined as ulcera-tive colitis extending proximal to the splenic flexure (E3) orCrohn’s colitis affecting at least 50% of surface area of the colon(L4).23 (See tables 3 and 4).

Patients with extensive colitis (ulcerative colitis or Crohn’sdisease) can be risk stratified as follows:< Lower risk: 5-yearly colonoscopy

eno endoscopic/histological active inflammation on theprevious colonoscopy (histological chronic or quiescentchanges acceptable) or

e left-sided colitis (any grade of inflammation) oreCrohn’s disease colitis affecting <50% surface area of thecolon (any grade of inflammation).

< Intermediate risk: 3-yearly colonoscopyemild endoscopic/histological active inflammation on theprevious surveillance colonoscopy or

e presence of post-inflammatory polyps ore family history of colorectal cancer in a first-degree relativeaged 50 years or over.

< Higher risk: yearly colonoscopyemoderate or severe endoscopic/histological active inflam-mation on the previous surveillance colonoscopy or

e stricture within past 5 years ore confirmed dysplasia within past 5 years in a patient whodeclines surgery or

e primary sclerosing cholangitis/post-orthotopic liver trans-plant for PSC or

e family history of colorectal cancer in a first-degree relativeaged <50 years

Recommendations for the surveillance of colonic carcinoma< The appropriateness of surveillance should be discussed with

patients who have ulcerative colitis or Crohn’s disease colitis

and a joint decision made on the balance of benefit to theindividual. The risk arising from ulcerative colitis and Crohn’sdisease colitis is similar.

< Index (screening) colonoscopy is advised for all patients withulcerative colitis or Crohn’s disease colitis at approximately10 years after onset of symptoms to reassess disease extent(EL2, RG C).

< Surveillance colonoscopies should be performed, wherepossible, when the disease is in remission. However,a surveillance procedure should not be unduly delayed ifremission cannot be achieved.

< Pancolonic dye spraying with targeted biopsy of abnormalareas is recommended. (EL2, RG A). If chromoendoscopy isnot used, the strategy of random biopsy outlined in the 2002surveillance guidelines should be followed.

< If a dysplastic polyp is detected within an area ofinflammation and can be removed in its entirety, it is notnecessary to recommend colectomy. Absence of dysplasia insurrounding tissue should be confirmed.

Post-colectomyThere is no clear evidence that pouch surveillance is beneficialand thus it cannot be strongly recommended. However, ifa clinician wishes to offer surveillance, the following surveillancepolicy would seem reasonable:< Higher-risk post-colectomy patients: consider yearly flexible

sigmoidoscopy of pouch/rectal mucosa in patients with:– previous rectal dysplasia or dysplasia or– colorectal cancer at the time of pouch surgery or– primary sclerosing cholangitis or– type C mucosa in the pouch (mucosa exhibiting permanentpersistent atrophy and severe inflammation).

< Lower-risk post-colectomy patients: consider 5-yearly flexiblesigmoidoscopy of pouch/rectal mucosa in patients with noneof the risk factors above.

Recommendations for pouch surveillance< Biopsies should be taken from pre-pouch ileum, the pouch-

anal anastomosis and the body of the pouch with fourbiopsies from each site. Pouch surveillance should be startedearly after pouch formation.

7.3 Management of pregnancy4

http://www.bsg.org.uk/forum (accessed Oct 2010)Inflammatory bowel disease is most commonly diagnosed in

the third and fourth decades and therefore it is not unusual tocare for females who are also pregnant. Approximately 25% offemale patients conceive after the diagnosis of IBD. Althoughfertility in inactive IBD is unaffected, active disease diminishesthis. This is further reduced by pelvic surgery or sepsis. Womenwith IBD are more likely to experience pre-term labour(<37 weeks duration) and low-birthweight babies (<2500 g).389

There is conflicting evidence regarding the frequency of foetalmalformations. Many of the adverse outcomes in pregnancy arerelated to active disease rather than the medicines given tocontrol this. Optimum disease control is necessary, ideally withremission prior to conception and active disease being treatedaggressively to ensure best possible outcomes. Flares should betreated aggressively to prevent adverse outcomes (EL3a, RG B).Active disease is a risk for pre-term delivery and low birthweight (EL3a, RG B). Insufficient data exist about maternalmorbidity and foetal mortality at surgery. Combined carebetween gastroenterologists and obstetricians is mandatory.The medical management of pregnancy in IBD requires careful

discussion with individual patients. There is a risk benefit ratio of

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each medicine taken that should be discussed ideally prior toconception. The Faculty of Sexual and Reproductive Health haveproduced clinical guidance that addresses fertility, pregnancy andcontraceptive choice in patients with IBD, (http://www.ffprhc.org.uk/admin/uploads/810_CEUGuidanceIBD09.pdf (accessedOct 2010)).

Medical treatment during pregnancyIn active disease during pregnancy the Food and Drug Admin-istration (FDA) pregnancy categories, ABCDX (see table) reflecta cautious approach. The drug description notice alwaysemphasises risks and side effects.

Food and drug administration (FDA) categories

The greatest risk to mother and fetus during pregnancy is activedisease, and not the medication used to treat it. In general,pharmacological treatment for active disease during pregnancy isthe same as for non-pregnant women.

Prescribing in pregnancy

Drugs used in IBD in pregnancy and breast feedingAminosalicylates (FDA B)Sulfasalazine and the other 5-ASA drugs (up to 3 g/day) are safein pregnancy and breast feeding. Sulfasalazine has the greatestclinical exposure. This leads to a reversible azospermia in men,there is a theoretical risk of neonatal haemolysis and it interfereswith the absorption of folic acid. Folate supplementation istherefore recommended (2 mg/day) for women taking sulfasa-lazine. The safety of higher doses of 5-ASA is more uncertain. Asingle observational study identified low birthweight and pre-term labour as consequences of treatment but the control groupdid not have IBD, a plausible explanation for this finding.Negligible amounts of 5-ASA are detected in breast milk asbreast feeding is thought to be safe. Watery diarrhoea has beendescribed in the infant but this usually ceases after withdrawingthe medicine.

Antibiotics (FDA B&C)In the UK antibiotic use in IBD is most commonly used forexacerbations of perianal Crohn’s disease. The most commonlyuse agents are metronidazole and ciprofloxacin. Metronidazole ismutagenic in some strains of bacteria and carcinogenic in miceafter long-term use but this has never been reported in humans.

Metronidazole is considered safe by most obstetricians afterthe first trimester. Two studies examining the effect of thefluoroquinolones on pregnancy have not identified any safetyissues. Tetracyclines and sulfonamides should be avoidedduring pregnancy. Relatively large amounts of metronidazoleare secreted in to breast milk and the manufacturer advisesavoiding large single doses. No adverse events have beenobserved in humans.390

Corticosteroids (FDA C)Corticosteroids vary in their ability to cross the placenta; 88% ofprednisolone is deactivated to a less active metabolite as itcrosses the placenta resulting in low fetal blood concentrations.If administration is prolonged or repeated in pregnancy there isa risk of intra-uterine growth retardation but there is noevidence of this following short-term administration. Althoughthe risk of cleft lip and palate, especially with first trimesterexposure is often cited391 the Committee on Safety of Medicines(CSM) in the UK concludes that there is no convincing evidenceof such congenital abnormalities being associated with cortico-steroids in humans. The balance of risks in mothers with activeIBD unresponsive to other treatments would favour treatmentwith steroids.Corticosteroids are excreted in small amounts in breast milk

but doses of prednisolone up to 40 mg daily are unlikely to causesystemic effects in the infant. Infants of mothers taking higherdoses may theoretically have a degree of adrenal suppression butthe benefits of breast feeding are likely to outweigh the risks. A4-h delay following oral exposure has been suggested to mini-mise exposure.

Budesonide (FDA C)No studies have been performed in patients with IBD but thetheoretical risks are those in the section above. The use ofinhaled budesonide would suggest that the drug is safe inpregnancy and breast feeding.

Thiopurines (FDA D)Although the manufacturers of AZA and MP advise avoiding inpregnancy there are considerable data, most of which come fromthe transplant and rheumatology literature, showing no alter-ations in fertility, pre-term delivery, or congenital defects. Thehigh FDA rating is based on human reports of high abortionrates. There are, however, relatively little direct patient dataavailable for IBD although that from the UK and US wouldsuggest no increase in adverse outcomes. A recent Scandinavianpopulation-based study of 900 children born to mothers withCrohn’s disease did suggest an increase risk of pre-term labourand congenital abnormalities in women exposed to both corti-costeroids and AZA/MP.392 The total numbers of women onthese medicines was relatively small and it was not possible todifferentiate between the effect of the drugs and that of activedisease. A single small study has suggested that when fathersused MP within three months of conception there was a higherincidence of pregnancy related complications. Therefore,although AZA and MP have FDA rating D, available data suggestthat these drugs are safe and well tolerated during pregnancy.This is corroborated by the British National Formulary.Furthermore, although breast feeding is not advised, emergingdata suggests there is very little exposure to the infant.393

Ciclosporin A (FDA C)Most available data regarding the use of ciclosporin in preg-nancy originates from transplant and rheumatology literature.

Considered safe Probably safe Contraindicated

Sulfasalazine (FDA B) Budesonide (FDA C) Methotrexate (FDA X)

Topical or oral mesalazine(FDA B)

Thiopurines (FDA D) Thalidomide (FDA X)

Corticosteroids (no rating) Infliximab (FDA B)Adalimumab

Tetracyclines (FDA D)

Olsalazine Diphenoxylate

Ciclosporin (FDA C)

Quinolones (FDA C) Metronidazole: avoid in firsttrimester

Tacrolimus (FDA C) Loperamide

A Controlled studies show no risk

B No evidence of risk in humans

C Risk cannot be ruled out, animal studiesshowed adverse effects on fetus

D Positive evidence of risk in humans, risk/benefit ratio should be considered

X Contraindicated

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There is a higher rate of prematurity and low birthweight, buta high survival rate. A recent series of eight patients with acutesevere ulcerative colitis did not identify any congenitalmalformations.394

Tacrolimus (FDA C)The transplant literature reports apparent safety. Preterm deliveryis more common, but no excess congenital malformations, lowbirth weight, or neonatal complications have been found.

Methotrexate (FDA X)Methotrexate (MTX) is teratogenic and toxic and is contra-indicated in pregnancy and breast feeding. If conception shouldaccidentally occur, therapeutic abortion should be discussed,although not mandatory. MTX should be stopped immediatelyand high-dose folic acid replacement started. The intracellularmetabolites of MTX, methotrexate polyglutamates, have a longhalf-life and take about 6 weeks to reach steady state or tocompletely wash out. Thus, women who wish to becomepregnant should stop MTX for 3�6 months. The same appliesto prospective fathers, to allow spermatogenesis return tonormal.

Anti-TNF therapy (FDA B) (adapted from ECCO consensus4)Although there are reports of the use of infliximab (IFX) andadalimumab (ADA) during pregnancy without apparentincreased risk long-term data are not available.395 396 Anti-TNFaantibodies are species specific. Murine models have failed toshow any teratogenicity or embryotoxicity. Case series from therheumatology and gastroenterology literature have suggestedgood outcomes in relatively small numbers of patients. Post-marketing data from Centocor of more than 280 pregnancies, ofwhich a third had IFX during the first trimester showed that75% had live births, 14% had a miscarriage, and 11% had ther-apeutic terminations.4

The long-term effects of anti-TNF therapy in utero ondevelopment, immune function and other biological program-ming are unknown. IFX and ADA are FDA Class B Risk Cate-gory in Pregnancy (similar to 5-ASA). Both are IgG1 antibodiesthat do not cross the placenta during the first trimester ofpregnancy. There is also limited data on anti-TNF excretion inbreast milk. Maternal transfer of IFX has been reported ina patient using 10 mgs/kg body weight throughout pregnancy.The drug was seen to persist in the baby for 6 months but it isnot known whether this induces antibody formation althoughthis would seem unlikely. Placental transfer of IFX was not seenin three mothers using 5 mg/kg up until week 30.397 Infantsexposed to anti-TNF therapy in utero are able to mount anappropriate immune response to vaccinations.

Of some concern is a recent analysis of the FDA databasedocumenting an increase in congenital abnormalities from theVACTERL spectrum262 in women taking etanercept or inflix-imab (see section 4.4.7). Although this finding has not beenconfirmed in further cohorts as yet, this demonstrates the needfor cautious use in pregnancy. There needs to be a carefuldiscussion of the risks and benefits with individual patients. Iftreatment is continued it would seem reasonable to stop afterthe second trimester and to avoid dose escalation to preventfoetal transfer.

Available data suggests that IFX cannot be detected in breastmilk and thus breast feeding would on the available data appearsafe. The implications of exposure to IFX on the newbornare unknown and a thorough discussion with patients ismandatory.

Recommendations for drugs used in pregnancy< Sulfasalazine should be stopped if there is suspected neonatal

haemolysis.< AZA should in general be continued during pregnancy, as the

risks to the fetus from disease activity appear to be greaterthan continued therapy. Babies born to mothers on AZA maybe lighter than normal and the riskebenefit should bediscussed with patients.

< Corticosteroids can be used for active disease, as the risks tothe pregnancy from disease activity are greater than fromcontinued therapy.

< MTX is absolutely contra-indicated in pregnancy.< Physicians should exercise caution when considering the

elective use of anti-TNF therapy in pregnant patients withIBD until further data become available regarding thefrequency of congenital abnormalities and long-termoutcomes. Conception should be discussed with women ofchildbearing age at the start of anti-TNF therapy. If treatedpatients present having become pregnant the treatmentshould be stopped after the second trimester.

Recommendations for the management of IBD in pregnancy< A gastroenterologist and obstetrician should manage preg-

nant women with IBD jointly.< Maintaining adequate disease control during pregnancy is

essential for both maternal and fetal health. If planningpregnancy, patients should be counselled to conceive duringremission and advised to continue their maintenancemedication. Prior to conception patients should be wellnourished and take folate supplements.

< Flexible sigmoidoscopy may be used safely where theinformation provided will significantly alter management.The least extensive procedure possible should be employed.

< Patients with acute severe colitis or other life-threateningcomplications of disease should be managed as for the non-pregnant patient, including abdominal radiograph. The bestinterests of the fetus are served by optimal management ofmaternal IBD.

< The mode of delivery should be carefully considered. Patientswith perianal Crohn’s disease or ileoanal pouch formationmay best have a caesarean section to avoid the risk of damageto the anal sphincter.

< Absolute indications for surgery are unaltered by pregnancyand surgery should only be delayed where aggressive medicaltherapy may allow critical foetal maturation.

< Intestinal resection should be covered by a defunctioningstoma. Primary anastomosis is best avoided.

7.4 Management of extra-intestinal manifestations398

http://www.bsg.org.uk/forum (accessed Oct 2010)Extra-intestinal manifestations (EIMs) are found in both

Crohn’s disease and ulcerative colitis, although they arecommoner in Crohn’s disease (particularly colitis and ileocolitis).The commonest EIMs are musculoskeletal and mucocutaneousforms including axial and peripheral arthritis, acute ocularinflammation, erythema nodosum and pyoderma gangrenosum.The most significant musculoskeletal manifestation is anky-losing spondylitis, which occurs in 1�5% of patients. Thisshould be managed jointly with a rheumatologist, and mayrequire biological therapy for the axial disease. In this case thechoice of biological agent should be discussed between gastro-enterologist and rheumatologist. Treatment for other EIMsconsists of treating the underlying bowel disease, symptomaticrelief and sometimes specific treatment of the EIM. Although

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sulfasalazine has a higher incidence of side-effects compared tonewer 5-ASA drugs, selected patients (such as those witha reactive arthropathy) may benefit (RG D). It is important totry to avoid using NSAIDs for symptom relief, particularly inthose patients with active gut disease. Peripheral arthritis iscommonly associated with active disease, and normallyresponds to treatment of the bowel disease. For more persistentsymptoms in the absence of active gut disease specific therapymay be required, including immune suppression and rarelybiological therapy. Erythema nodosum is the commonestcutaneous manifestation, is usually associated with activedisease, and responds well to treatment of the gut disease.Pyoderma gangrenosum is rare, but difficult to treat and oftenrequires treatment with calcineurin inhibitors or biologicaltherapy. For acute ocular manifestations patients should bereferred for ophthalmological assessment before startingtherapy.

7.5 Primary sclerosing cholangitis399

http://www.bsg.org.uk/forum (accessed Oct 2010)Liver biochemistry may be abnormal in up to a third of patient

with defined IBD.400 Of this only 6% have a defined liver diseaseof which primary sclerosing cholangitis (PSC) is the commonest(4.6%). Conversely, 70% of PSC patients have associated IBD.PSC is a rare but serious liver disease (incidence approximately1:100 000 population/year). From diagnosis, the average survivalvaries from 12 to 17 years. High proportions of patients developcirrhosis and require liver transplantation. There is a 5e15%lifetime risk of cholangiocarcinoma, which carries a poor prog-nosis. (See BSG guidelines on diagnosis and treatment of chol-angiocarcinoma.)401 Several studies have indicated those patientswith concomitant PSC are at a higher risk of colorectalneoplasia.385 402 The absolute cumulative risk of cancer ordysplasia in this subset of patients has been estimated to be 9%after 10 years, 31% after 20 years, and 50% after 25 years ofcolitis.403 Patients with PSC often have quiescent colitis and so itis difficult estimating the exact onset of ulcerative colitis in thisgroup. For the above reasons it is recommended such patientsshould have annual surveillance colonoscopy.384 The diagnosis ofPSC is suggested by raised liver alkaline phosphatase, pANCA+,or changes of periductular fibrosis on liver biopsy. The diagnosisrequires stricturing and dilatation of the intra- and/or extra-hepatic bile ducts on imaging. Magnetic resonance cholangiog-raphy (MRCP) avoids the risks of ERCP. Liver biopsy is necessaryfor diagnosis of small duct disease.

Ursodeoxycholic acid (UDCA) improves liver biochemistryand at high dose may improve survival probability.404 However,a recent large RCT was stopped early due to excess adverseevents in the group receiving high dose UDCA.405 Thereforehigh dose UDCA may be harmful.406 UDCA appears to reducethe risk of bowel cancer.407 408 Treatment of dominant stricturesby ERCP and dilatation may be indicated and liver transplant isindicated for end stage liver disease.

7.6 Osteoporosis and osteomalaciaBoth osteoporosis and vitamin D deficiency (includingcompensated deficiency states with normal calcium and highparathyroid hormone) are common in IBD. The major riskfactors for osteoporosis complicating IBD are age, steroid useand disease activity. The reader is referred to the 2007 BSGguidelines for osteoporosis in IBD and coeliac disease for acomprehensive review (http://www.bsg.org.uk/pdf_word_docs/ost_coe_ibd.pdf (last accessed Oct 2010)) along with the guide-lines of the Royal College of Physicians (http://bookshop.

rcplondon.ac.uk/contents/pub89-a953a6c0-06c0-46d8-b79a-e951536d9070.pdf (last accessed Oct 2010)).

Recommendations for osteoporosis and osteomalacia:< Supplementation of calcium and vitamin D is recommended

when systemic steroid use is necessary (EL3, RG C).< Co-administration of bisphosphonates with steroids is

recommended for patients aged over 65 years or withknown osteoporosis/osteopenia. Unless advised on othergrounds, the bisphosphonate should only be given whilethe patient is on steroids (EL4, RG C).

7.7 Anaemiahttp://www.bsg.org.uk/forum (accessed Oct 2010)Anaemia is a common complication of IBD.409 Comprehen-

sive guidelines have recently been published from an expertworking group.410 Iron deficiency and anaemia of chronic diseaseare the commonest causes of anaemia in IBD, though folate andvitamin B12 deficiency occur. Drug-induced anaemia secondaryto AZA, MP or sulfasalazine also occurs. Other coexisting causesof anaemia such as menorrhagia and coeliac disease should besought by careful history taking and use of coeliac serologicaltesting. In older patients and those with a family history ofcancer, investigation should exclude bowel cancer as a cause.

Screening for anaemiaPatients with IBD should have at least annual haemoglobincheck. The ferritin, transferrin saturation and CRP should bechecked in anaemic patients or those with low MCV. The CRP isimportant to interpret the ferritin level as ferritin can be elevatedin an acute phase reaction. Levels of ferritin less than 100 mg/lare suggestive of iron deficiency.411 Those patients with smallbowel disease at risk of folate or B12 malabsorption or witha macrocytosis should have levels of B12 and folate checked.

Treatment of iron deficiencyLong-term prevention of anaemia by treatment of underlyingIBD is primary412 but iron replacement is also needed andimproves quality of life. Treatment may be with oral iron, (eg,ferrous sulfate 200 mg bd or another preparation with equalamounts of elemental iron, c. 130 mg/day), but this may not betolerated well and may exacerbate IBD symptoms measured byactivity scores. In patients with poor tolerance to oral iron,intravenous replacement is preferred. Iron sucrose (Venofer),ferric carboxy-maltose (Ferinject) do not have the magnitude ofrisk of anaphylaxis of iron dextran and are generally well toler-ated and usually effective.413e415

Other anaemiasB12 and folate deficiency may occur in Crohn’s disease andreplacement with oral folate and IM B12 is appropriate. Theneed for B12 replacement therapy should be anticipated inpatients who have had ileal resections (see section 6.6.5).Monitoring or early replacement should be instituted. Thio-purines also cause macrocytosis and anaemia. If vitamin levelsand iron are normal then drug-induced anaemia should beconsidered. Referral for haematology opinion and bone marrowexamination may be necessary along with the consideredwithdrawal of any implicated drug treatment.

Non-responsive anaemiaIn patients with IBD and severe anaemia that is non responsiveto iron therapy there is good evidence to show that erythro-poietin analogue therapies will produce a response in 70�100%

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of patients.410 416 Cost, however, is a limiting factor and recentUK NICE guidelines for anaemia induced by cancer therapy havelimited the use in the context of cancer chemotherapy topatients unable to have transfusions and with Hb of less than8 g/dl. The cost in 2008 was from £188 to £234 per week. (NICEtechnology appraisal guidance 142: Epoetin alfa, epoetin b anddarbepoetin alfa for cancer treatment-induced anaemia; www.nice.org.uk/TA142 (last accessed Oct 2010)).

7.8 Vaccinationshttp://www.bsg.org.uk/forum (accessed Oct 2010)

Patients with IBD may be at risk for infections due tounderlying disease, malnutrition, surgery, or immunosuppressivetherapy. The available data on the incidence and prevention ofopportunistic infections in IBD has recently been published andsummarised in a leading article in Gut.277 417

7.8.1 Infection and immunisation historyA vaccine and infection history is best taken at baseline whena patient is diagnosed with IBD, including TB exposure, chick-enpox history and risk of hepatitis B. Varicella zoster serology isbest checked if there is no history of infection. We recommendchecking hepatitis B serology in high-risk patients and prior toanti-TNF therapy (see section 4.4.7). If patients are sero-positivefor hepatitis B, please refer to the ECCO consensus document onprevention, diagnosis and management of opportunistic infec-tions in IBD for guidance.277

7.8.2 Recommended vaccinations< Influenza, pneumococcal and HPV (females) vaccination is

generally recommended for immunosuppressed adults and isbest considered for all patients with IBD, given the frequentneed for steroid and immunosuppressive therapy. Boostervaccinations are appropriate for influenza (annually) andpneumococcus (after 3 years).418

< Hep B vaccinations should be considered prior to immuno-suppressive or anti-TNF monoclonal antibody therapy in thenon immune high-risk patient.

< Live vaccines should be avoided in patients on immunosup-pression or steroids (MMR, oral polio, yellow fever, livetyphoid, varicella, BCG).

< Varicella vaccination before treatment with steroids orimmunosuppressants is now a possibility and has beenrecommended in Europe and the USA in the non-immune.

7.8.3 Post-exposure prophylaxisPost-exposure prophylaxis of varicella and measles exposed non-immune individuals on high-dose steroid or immunosuppressionis appropriate with immune globulin (varicella zoster immu-noglobulin or human normal immunoglobulin).418 Aciclovirprophylaxis may also be used for varicella.

Recommendations for vaccinations< A vaccination and infection history should be taken in all

patients with IBD (EL5, RG D).< Primary and booster vaccination for influenza and pneumo-

coccus should be offered to immunosuppressed patients withIBD.

7.9 Psychological aspectshttp://www.bsg.org.uk/forum (accessed Oct 2010).

7.9.1 Incidence and prevalence of mood disorders in IBDThe incidence of depressive illness is higher in IBD cohorts thancontrol populations with a reported OR of 2.2 (lifetime preva-

lence in IBD 27%419 and 12 month point prevalence 15%.420

Anxiety is also more common in patients with IBD than incontrols.421 Mood disorders in patients with IBD are at least inpart a consequence of the IBD itself422 and its medical treatment(eg, corticosteroid therapy); surgery, including specificallycolectomy and stoma formation also have psychosocial impli-cations as do awareness of the risk of cancer and cancersurveillance.

7.9.2 Psychological stress as a trigger for disease or relapse?Human and animal studies have revealed psycho-neuro-immunological mechanisms whereby stress could influence thecourse of IBD.423 Stress and adverse life events do not appear totrigger the onset of Crohn’s disease or ulcerative colitis, but mostreports indicate that they may be involved in triggering relapseof IBD.424 425 Furthermore, behaviour limiting exposure tostressful situations is associated with reduced symptomaticrelapse, at least in Crohn’s disease.426

7.9.3 Effectiveness of psychological support in IBDThe effectiveness of psychological interventions has beenreviewed by ECCO for both ulcerative colitis and Crohn’sdisease.4 5 Evidence indicates that psychosocial support is useful,particularly in adolescents.There is no definitive evidence thatpsychological interventions improve the course of IBD itself butthey do usually improve patients’ quality of life and well-being.427 428 In general, psychological and psychiatric supportshould be made available where psychological concerns arepresent. (The psychological care of medical patients: A practicalguide. Royal College of Physicians Royal College of PsychiatristsReport of a joint working party of the Royal College of Physi-cians and the Royal College of Psychiatrists Second edition 2003http://www.rcplondon.ac.uk/pubs/wp/wp_pcomp.pdf (lastaccessed Oct 2010); IBD Service standards http://www.ibdstandards.org.uk. IBD nurses may play an important role inthis regard either with formal training or informally.

IBD service standard< Psychological support should be available to patients with

IBD (IBD Standard A2).

7.10 Inflammatory bowel disease in childrenhttp://www.bsg.org.uk/forum (accessed Oct 2010)Guidelines produced by the British Society of Paediatric

Gastroenterology, Hepatology and Nutrition can be accessedfrom the society website: http://www.bspghan.org.uk/ (lastaccessed Oct 2010).Information for parents and patients is available from the

Crohn’s in Childhood Research Association (CICRA) www.cicra.org (accessed Oct 2010).

7.11 Management of adolescents (transitional care)http://www.bsg.org.uk/forum (accessed Oct 2010)Guidelines for transition of patients with IBD were published

by CICRA and NACC in 2008 www.nacc.org.uk (accessed Oct2010). There are three separate documents for the professionals,parents and the patients.

DefinitionTransition is the planned move of adolescents and young adultswith IBD from child-centred to adult-orientated healthcare andis a process, not a single event. Transfer is the successful hand-over of care to adult services.429 The National Service Frame-work for Children, Young People and Maternity Services’guidance defines transition as:

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‘A purposeful, planned process that addresses the medical,psychosocial and educational/vocational needs of adolescents andyoung adults as they move from child-centred to adult-orientedhealthcare systems.’ (Department of Health Transition: Getting itright for young people. National Service Framework for Children,Young People and Maternity Services, 2006) http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/Browsable/DH_4132944 (accessed Oct 2010).

The principles that inform the guidelinesYoung people with IBD have a right to a managed transitionprocess when moving from paediatric to adult care. They shouldbe continuously prepared for transition throughout their teensto ensure they are ready for formal transfer of care to the adultservices. Transition should not compromise the young person’scurrent care or their treatment options. It begins in paediatricservices but adult services bear responsibility for its successfulcompletion.

Many factors are important in timing the transfer from childto adult care. The young person (and parents if the young personwishes) should be involved or represented in planning theirtransition. Young people need well-developed social, interper-sonal and emotional skills to successfully enter the world ofadult healthcare.

Transition works best when it is coordinated and overseenby a nominated key worker or coordinator430 (Department ofHealth. Getting the right start: National Service Frameworkfor Children. Standard for Hospital Services.2003 paras4.58e4.62, http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_4006182(accessed Oct 2010)).

Care plans including details of investigations and treatmentstried successfully or otherwise must be drawn up. Multidisci-plinary teams of paediatric and adult health professionalsworking together should provide transitional care. (Departmentof Health. National Service Framework for Children, YoungPeople and Maternity Services. Core Standards. 2004) (see linkabove).

IBD service standard: (Standard A12)< There must be a defined policy and protocol for transitional

care.< A named co-ordinator should be responsible for the prepara-

tion and oversight of transition (eg, IBD nurse specialist).

Acknowledgements The authors would like to thank Belinda Theis for assistingwith literature searches, editorial meetings and proof reading. We thank SimonTravis for making the revised set of ECCO consensus statements available ahead oftheir publication.

Competing interests Dr Craig Mowat has received support to attend academicmeetings from Abbott, Shire, Ferring and UCB, and has sat on advisory boards forAbbott, Shire, and Ferring. He has received honoraria from Schering-Plough, Shire andFerring for presentations at academic meetings. Dr A.T. Cole has received educationalgrants from Abbott, Scherring-Plough, Ferring and Dr Falk Ag in support of conferenceattendance and to support educational meetings and has been on advisory boards forSchering-Plough and Ferring. Dr Ian Arnott has sat on advisory boards for Abbott andSchering-Plough. He has received support to attend academic meetings from Abbott,Shire, and Proctor and Gamble. He has also received honoraria from Abbott,Schering-Plough, Shire and Ferring for presentations at academic meetings. ProfessorJack Satsangi has acted as a consultant to Schering-Plough, Abbott, UCB, Shire andFerring, and has on-going research support from Novartis and Genentech. Dr MattRutter has received support to attend academic meetings from Abbott, Shire andProctor and Gamble. He has also received honoraria from Shire, Proctor and Gamble,and Ferring for presentations at academic meetings. Dr Tim Orchard has sat onadvisory boards for, and has received support to attend academic meetings fromAbbott, Schering-Plough, Dr Falk Pharma, Ferring, Procter and Gamble, Shire and UCB.He has received honoraria from Ferring, Abbott, Schering-Plough, Procter and Gamble,and Shire. He has on-going research support form Johnson and Johnson. Dr Gwo-Tzer

Ho has received support to attend academic meetings from Abbott, Schering-Plough,Shire, and Proctor and Gamble. He has also received honoraria from Abbott, Shire,Otsuka Pharmaceuticals and Astra Zeneca for presentations at academic meetings. DrCharlie Lees has acted as a consultant to Abbott and Dr Falk, and received honorariafrom Shire, Procter and Gamble, Ferring, and Schering-Plough for presentations atacademic meetings. Mr Alastair Windsor has received support to attend academicmeetings from Proctor and Gamble. He has sat on advisory boards for Procter andGamble and Ferring. He has also received honoraria from Abbott, Proctor and Gamble,and Ferring for presentations at academic meetings. Dr Stuart Bloom has acted asa consultant for and sat on advisory boards for Abbott, Shering-Plough, Shire, Ferring,Proctor and Gamble. He has received honoraria from Shering-Plough for chairingsymposia.

Provenance and peer review Not commissioned; externally peer reviewed.

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